Academic literature on the topic 'Molecular receptors'
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Journal articles on the topic "Molecular receptors"
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Brown, Michael, Michael Webb, Elsa Phillips, Elizabeth Skidmore, and Peter McIntyre. "Molecular studies on kinin receptors." Canadian Journal of Physiology and Pharmacology 73, no. 7 (July 1, 1995): 780–86. http://dx.doi.org/10.1139/y95-105.
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We describe the results of functional studies on DNA clones encoding functional bradykinin receptors derived from human, rat, and mouse sources and including both genomic and complementary DNA clones. In both the Xenopus oocyte and the COS cell expression systems, the receptors from human and rat showed the pharmacological properties of B2 receptors, but receptors from mouse displayed both B1- and B2-like pharmacological properties. We further investigated the molecular relationship between the B1 and B2 receptor subtypes expressed by a human fibroblast cell line, and we demonstrate that these two receptor subtypes are encoded by distinct mRNA species.Key words: B1 receptor, antisense, Xenopus oocyte.
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Szybowska, Patrycja, Ellen Margrethe Haugsten, and Antoni Wiedlocha. "The canonical FGF-FGFR signaling system at the molecular level." Postępy Higieny i Medycyny Doświadczalnej 75, no. 1 (January 1, 2021): 711–19. http://dx.doi.org/10.2478/ahem-2021-0024.
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Abstract Extracellular signaling molecules, among them the fibroblast growth factors (FGFs), enable cells to communicate with neighboring cells. Such signaling molecules that receive and transmit a signal require specific tyrosine kinase receptors located at the cell surface (fibroblast growth factor receptors, FGFRs). The binding of a signaling molecule to its specific receptor results in receptor dimerization and conformational changes in the cytoplasmic part of the receptor. The conformational changes lead to trans-autophosphorylation of the tyrosine kinase domains of the receptors and subsequently to induction of several downstream signaling pathways and expression of appropriate genes. The signaling pathways activated by FGFs control and coordinate cell behaviors such as cell division, migration, differentiation, and cell death. FGFs and their transmembrane receptors are widely distributed in different tissues and participate in fundamental processes during embryonic, fetal, and adult human life. The human FGF/FGFR family comprises 22 ligands and 4 high affinity receptors. In addition, FGFs bind to low affinity receptors, heparan sulfate proteoglycans at the cell surface. The availability of appropriate ligand/receptor pair, combined with the co-receptor, initiates signaling. Inappropriate FGF/FGFR signaling can cause skeletal disorders, primarily dwarfism, craniofacial malformation syndromes, mood disorders, metabolic disorders, and Kallman syndrome. In addition, aberrations in FGF/FGFR signaling have already been reported in several types of malignant diseases. Knowledge about the molecular mechanisms of FGF/FGFR activation and signaling is necessary to understand the basis of these diseases.
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Hay, D. L., G. Christopoulos, A. Christopoulos, and P. M. Sexton. "Amylin receptors: molecular composition and pharmacology." Biochemical Society Transactions 32, no. 5 (October 26, 2004): 865–67. http://dx.doi.org/10.1042/bst0320865.
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Several receptors which bind the hormone AMY (amylin) with high affinity have now been identified. The minimum binding unit is composed of the CT (calcitonin) receptor at its core, plus a RAMP (receptor activity modifying protein). The receptors have been named AMY1(a), AMY2(a) and AMY3(a) in accordance with the association of the CT receptor (CT(a)) with RAMP1, RAMP2 and RAMP3 respectively. The challenge is now to determine the localization and pharmacological nature of each of these receptors. Recent attempts to achieve these aims will be briefly discussed.
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Alfimov, Michael V., Olga A. Fedorova, and Sergey P. Gromov. "Photoswitchable molecular receptors." Journal of Photochemistry and Photobiology A: Chemistry 158, no. 2-3 (June 2003): 183–98. http://dx.doi.org/10.1016/s1010-6030(03)00033-9.
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Xie, Peng, Junjie Zhang, Baiyu Chen, Xinwei Li, Wenbo Zhang, Mengdan Zhu, Wei Li, Jianqi Li, and Wei Fu. "Computational Methods for Understanding the Selectivity and Signal Transduction Mechanism of Aminomethyl Tetrahydronaphthalene to Opioid Receptors." Molecules 27, no. 7 (March 28, 2022): 2173. http://dx.doi.org/10.3390/molecules27072173.
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Opioid receptors are members of the group of G protein-couple receptors, which have been proven to be effective targets for treating severe pain. The interactions between the opioid receptors and corresponding ligands and the receptor’s activation by different agonists have been among the most important fields in opioid research. In this study, with compound M1, an active metabolite of tramadol, as the clue compound, several aminomethyl tetrahydronaphthalenes were designed, synthesized and assayed upon opioid receptors. With the resultant compounds FW-AII-OH-1 (Ki = 141.2 nM for the κ opioid receptor), FW-AII-OH-2 (Ki = 4.64 nM for the δ opioid receptor), FW-DI-OH-2 (Ki = 8.65 nM for the δ opioid receptor) and FW-DIII-OH-2 (Ki = 228.45 nM for the δ opioid receptor) as probe molecules, the structural determinants responsible for the subtype selectivity and activation mechanisms were further investigated by molecular modeling and molecular dynamics simulations. It was shown that Y7.43 was a key residue in determining the selectivity of the three opioid receptors, and W6.58 was essential for the selectivity of the δ opioid receptor. A detailed stepwise discovered agonist-induced signal transduction mechanism of three opioid receptors by aminomethyl tetrahydronaphthalene compounds was proposed: the 3–7 lock between TM3 and TM7, the DRG lock between TM3 and TM6 and rearrangement of I3.40, P5.50 and F6.44, which resulted in the cooperative movement in 7 TMs. Then, the structural relaxation left room for the binding of the G protein at the intracellular site, and finally the opioid receptors were activated.
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Breyer, M. D., H. R. Jacobson, and R. M. Breyer. "Functional and molecular aspects of renal prostaglandin receptors." Journal of the American Society of Nephrology 7, no. 1 (January 1996): 8–17. http://dx.doi.org/10.1681/asn.v718.
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The diverse intrarenal effects of the prostaglandins (PG) are mediated by distinct guanine nucleotide regulatory protein (G-protein)-coupled receptors. The cDNA for these receptors have been cloned, their signal transduction mechanisms determined, and their intrarenal distribution mapped. PGE2, the major intrarenal prostaglandin, interacts with at least three distinct E-prostanoid (EP) receptors that are highly expressed in specific regions of the kidney. Each EP receptor not only selectively binds PGE2, but also preferentially couples to different signal transduction pathways, including: stimulation of cAMP generation, via Gq (EP2 and EP4 receptors); inhibition of cAMP generation, via Gi (EP3 receptors); and activation of phosphatidylinositol hydrolysis (EP1 receptor), via one of the Gq family members. Activation of each these EP receptors is responsible for a distinct renal effect of PGE2, including its well-described renal hemodynamic and transport effects along the nephron. Other intrarenal prostanoid receptors include the PGF2 alpha receptor (FP), the thromboxane A2 receptor (TP) and the prostacyclin receptor (IP). Knowledge about localization of these receptors and their affinities for receptor-selective agonists and antagonists should aid in the understanding of renal disease and the development of therapeutic strategies for the use of these prostaglandin analogs in select renal diseases.
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North, R. Alan. "Molecular Physiology of P2X Receptors." Physiological Reviews 82, no. 4 (January 10, 2002): 1013–67. http://dx.doi.org/10.1152/physrev.00015.2002.
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P2X receptors are membrane ion channels that open in response to the binding of extracellular ATP. Seven genes in vertebrates encode P2X receptor subunits, which are 40–50% identical in amino acid sequence. Each subunit has two transmembrane domains, separated by an extracellular domain (∼280 amino acids). Channels form as multimers of several subunits. Homomeric P2X1, P2X2, P2X3, P2X4, P2X5, and P2X7channels and heteromeric P2X2/3and P2X1/5channels have been most fully characterized following heterologous expression. Some agonists (e.g., αβ-methylene ATP) and antagonists [e.g., 2′,3′- O-(2,4,6-trinitrophenyl)-ATP] are strongly selective for receptors containing P2X1and P2X3subunits. All P2X receptors are permeable to small monovalent cations; some have significant calcium or anion permeability. In many cells, activation of homomeric P2X7receptors induces a permeability increase to larger organic cations including some fluorescent dyes and also signals to the cytoskeleton; these changes probably involve additional interacting proteins. P2X receptors are abundantly distributed, and functional responses are seen in neurons, glia, epithelia, endothelia, bone, muscle, and hemopoietic tissues. The molecular composition of native receptors is becoming understood, and some cells express more than one type of P2X receptor. On smooth muscles, P2X receptors respond to ATP released from sympathetic motor nerves (e.g., in ejaculation). On sensory nerves, they are involved in the initiation of afferent signals in several viscera (e.g., bladder, intestine) and play a key role in sensing tissue-damaging and inflammatory stimuli. Paracrine roles for ATP signaling through P2X receptors are likely in neurohypophysis, ducted glands, airway epithelia, kidney, bone, and hemopoietic tissues. In the last case, P2X7receptor activation stimulates cytokine release by engaging intracellular signaling pathways.
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Livingstone, C. D., P. G. Strange, and L. H. Naylor. "Molecular modelling of D2-like dopamine receptors." Biochemical Journal 287, no. 1 (October 1, 1992): 277–82. http://dx.doi.org/10.1042/bj2870277.
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Three-dimensional computer models of the rat D2, D3 and D4 dopamine receptor subtypes have been constructed based on the diffraction co-ordinates for bacteriorhodopsin, another membrane-bound protein containing seven transmembrane domains presumed to be arranged in a similar spatial orientation. Models were assembled by aligning the putative transmembrane domains of the dopamine receptors with those of bacteriorhodopsin using sequence similarities, and then superimposing these modelled alpha-helices on to the bacteriorhodopsin-derived co-ordinates. These models explore the potential hydrogen bonding, electrostatic and stacking interactions within the receptor which may be important for maintaining the conformation of these receptors, and thereby provide target sites for agonist binding. Proposed interactions between the catecholamine ligands and these receptors appear to account for the affinity, although not the specificity, of these agonist ligands for the different dopamine receptor subtypes. Such models will be useful for establishing structure-function relationships between ligands and the dopamine receptors, and may ultimately provide a template for the design of receptor-specific drugs.
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Behzadi, Payam, Herney Andrés García-Perdomo, and Tomasz M. Karpiński. "Toll-Like Receptors: General Molecular and Structural Biology." Journal of Immunology Research 2021 (May 29, 2021): 1–21. http://dx.doi.org/10.1155/2021/9914854.
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Background/Aim. Toll-like receptors (TLRs) are pivotal biomolecules in the immune system. Today, we are all aware of the importance of TLRs in bridging innate and adaptive immune system to each other. The TLRs are activated through binding to damage/danger-associated molecular patterns (DAMPs), microbial/microbe-associated molecular patterns (MAMPs), pathogen-associated molecular patterns (PAMPs), and xenobiotic-associated molecular patterns (XAMPs). The immunogenetic molecules of TLRs have their own functions, structures, coreceptors, and ligands which make them unique. These properties of TLRs give us an opportunity to find out how we can employ this knowledge for ligand-drug discovery strategies to control TLRs functions and contribution, signaling pathways, and indirect activities. Hence, the authors of this paper have a deep observation on the molecular and structural biology of human TLRs (hTLRs). Methods and Materials. To prepare this paper and fulfill our goals, different search engines (e.g., GOOGLE SCHOLAR), Databases (e.g., MEDLINE), and websites (e.g., SCOPUS) were recruited to search and find effective papers and investigations. To reach this purpose, we tried with papers published in the English language with no limitation in time. The iCite bibliometrics was exploited to check the quality of the collected publications. Results. Each TLR molecule has its own molecular and structural biology, coreceptor(s), and abilities which make them unique or a complementary portion of the others. These immunogenetic molecules have remarkable roles and are much more important in different sections of immune and nonimmune systems rather than that we understand to date. Conclusion. TLRs are suitable targets for ligand-drug discovery strategies to establish new therapeutics in the fields of infectious and autoimmune diseases, cancers, and other inflammatory diseases and disorders.
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Bettler, Bernhard, Klemens Kaupmann, Johannes Mosbacher, and Martin Gassmann. "Molecular Structure and Physiological Functions of GABAB Receptors." Physiological Reviews 84, no. 3 (July 2004): 835–67. http://dx.doi.org/10.1152/physrev.00036.2003.
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GABAB receptors are broadly expressed in the nervous system and have been implicated in a wide variety of neurological and psychiatric disorders. The cloning of the first GABAB receptor cDNAs in 1997 revived interest in these receptors and their potential as therapeutic targets. With the availability of molecular tools, rapid progress was made in our understanding of the GABAB system. This led to the surprising discovery that GABAB receptors need to assemble from distinct subunits to function and provided exciting new insights into the structure of G protein-coupled receptors (GPCRs) in general. As a consequence of this discovery, it is now widely accepted that GPCRs can exist as heterodimers. The cloning of GABAB receptors allowed some important questions in the field to be answered. It is now clear that molecular studies do not support the existence of pharmacologically distinct GABAB receptors, as predicted by work on native receptors. Advances were also made in clarifying the relationship between GABAB receptors and the receptors for γ-hydroxybutyrate, an emerging drug of abuse. There are now the first indications linking GABAB receptor polymorphisms to epilepsy. Significantly, the cloning of GABAB receptors enabled identification of the first allosteric GABAB receptor compounds, which is expected to broaden the spectrum of therapeutic applications. Here we review current concepts on the molecular composition and function of GABAB receptors and discuss ongoing drug-discovery efforts.
Dissertations / Theses on the topic "Molecular receptors"
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Björnström, Linda. "Molecular mechanisms of alternative estrogen receptor signaling /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-509-3/.
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Kovoor, Abraham. "Molecular regulation of opioid receptors /." Thesis, Connect to this title online; UW restricted, 1998. http://hdl.handle.net/1773/6278.
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Meira, Guilherme Louzada Silva. "Analíse da expressão do receptor olfativo M93 em sistemas heterólogos." Universidade de São Paulo, 2004. http://www.teses.usp.br/teses/disponiveis/46/46131/tde-31082016-115408/.
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O sistema olfatório de mamífero pode discriminar milhares de odores presentes no meio ambiente. Aproximadamente 1000 diferentes receptores olfatórios (ORs) são expressos no epitélio olfatório (OE) do nariz, Os ORs detectam os odores e transmitem os sinais resultantes para o bulbo olfatório (OB) no cérebro. Os ORs pertencem a super família dos receptores acoplados a proteína G (GPCR) e apresentam sete domínios transmembrânicos putativos. Por razões desconhecidas, os ORs são retidos no retículo endoplasmático quando expressos em linhagens de células de mamíferos heterólogas. Provavelmente, proteínas acessórias sejam requeridas para o endereçamento dos Ors para a superficie celular. No presente estudo, utilizamos o OR M93 para estudar os mecanismos de expressão de um ORo A dissertação teve como objetivos específicos: (l) construção de um vetor para expressão do OR M93 em fusão com GFP em levedura e análise de sua localização celular; (2) identificar proteínas expressas no epitélio olfatório de camundongo que interajam com os ORs. A análise por microscopia de fluorescência revelou que a expressão do OR M93 fusionado a GFP demonstrou um padrão de fluorescência que sugere a retenção do OR M93 no retículo endoplasmático. Nós utilizamos o sistema de duplo híbrido em levedura para varrer uma biblioteca de cDNA de epitélio olfatório de camundongo com uma isca correspondente à região N-terminal do OR M93. Quatro proteínas candidatas foram identificadas: HLA-B associado ao transcrito 3 (BAT-3/ Scythe), superfamília transmembrana 4 (membro CD82), superfamília transmembrana 4 (membro OAP-I) e sindecan (membro SDC2) (\"GenBank accession numbers\": BC026647, D14883, BC0430n e BC047144). A análise da hibridação in situ destas proteínas, revelou que a proteína OAP-1 é a melhor candidata a interação com OR M93. Dessa maneira, nós indicamos a proteína OAP-1 como possível proteína candidata a auxiliar o OR a ser expresso de maneira funcional em sistemas heterólogos.The mammalian olfactory system can discrim inate thousands of odorants present in the environrnent. Approximately 1000 different olfactory receptors (ORs) are expressed in the olfactory epithelium (OE) of the nose. The ORs detect odorants and transmit the resulting signals to the olfactory bulb (OB) of the brain. ORs belong to the G-protein-coupled receptor (GPCR) super family and have seven putative transmembrane domains. For unknown reasons, the ORs are retained in the endoplasmatic reticulum when expressed in heterologous mammalian cell lines. Probably accessory proteins are required for the sorting of the ORs to the cell surface. In the present work, we used the OR M93 to study the mechanisms of OR expression. Our goals were to (1) construct an expression vector for OR M93 in fusion with GFP in yeast and (2) to identify proteins expressed in the mouse OE that interact with ORs. The analysis by fluorescence microscopy suggested that OR M93 in fusion with GFP was retained in the endoplasmic reticulum (ER) of yeast. We used the yeast two-hybrid system to screen a mouse OE cDNA library with a bait corresponding to the N-terminal region ofthe üR M93. Four potential candidates were identified: HLA-B associated transcript 3 (BAT-3/Scythe), transmembrane 4 superfamily (CD82 member), transmembrane 4 superfamily (TSPN-3 member) and syndecan (SDC2). In situ hybridization analysis suggests that OAP-l protein represents the best candidate for interaction with OR M93. We suggest the OAP-l protein could be an accessory protein required for the sorting of the ORs to the cell surface in heterologous cell lines.
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McGinley, Paula Lynn. "Molecular complementation of mutant hormone receptors." Access to citation, abstract and download form provided by ProQuest Information and Learning Company; downloadable PDF file, 189 p, 2008. http://proquest.umi.com/pqdweb?did=1456289611&sid=5&Fmt=2&clientId=8331&RQT=309&VName=PQD.
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Kuswandi, Susi Iravati. "Molecular genetic analysis of aerobactin receptors." Thesis, University of Leicester, 1996. http://hdl.handle.net/2381/34438.
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Some Enterobacteriaceae produce a low molecular weight compound, aerobactin, with a high affinity for ferric iron. The genes encoding the aerobactin system have been identified in plasmid or chromosomal DNA; they are arranged in an operon consisting of five genes; four genes encode enzymes responsible for the biosynthesis of aerobactin and the fifth encodes an outer membrane receptor protein specific for ferric aerobactin. The aerobactin receptor protein appears to be different in size (molecular weight) in different species. Escherichia coli (ColV-K30) express a 74 kDa protein, while Shigella spp. express a 76 kDa protein. The aerobactin receptor protein also acts as a receptor for the bacteriocin cloacin DF13. Shigella spp. expressing the aerobactin receptor protein were less sensitive to cloacin DF13 than E. coli (ColV-K30). The aerobactin receptor genes of several Shigella spp. isolate have been cloned and the aerobactin receptor gene from Shigella flexneri ser.6 {iutAsh) has been sequenced. The restriction maps of iutAsh and iutA (aerobactin receptor gene from ColV-K30) were similar. The main difference was the existence of a BamHI site in the middle of iutAsh but not in iutA. The predicted protein product of iutAsh consists of 732 amino acid residues, the same as the aerobactin receptor protein from ColV-K30 (iutA), and with 93% similarity. Construction of iutA::iutAsh hybrid genes demonstrated that although verious parts of iutA were able to increase the cloacin sensitivity function of iutAsh, the main function was located in the 3'-terminus of iutA. Constructs with the 3'-terminus of iutA expressed a 74 kDa, while constructs with 3'-terminus of iutAsh expressed a 76 kDa outer membrane protein. The aerobactin uptake of E. coli strains carrying constructs with the 3'-terminus of iutAsh was higher than that of E. coli strains carrying constructs with the 3'-terminus of the iutA. The highest aerobactin uptake was showed by E. coli strain carrying construct 2, which consist of the iutA fragment upstream of the ClaI site and the iutAsh fragment downstream of the ClaI site. Bacteriophage B74K was capable of using the aerobactin receptor protein, but it was also capable of using other outer membrane proteins as receptors, and so could not be used for aerobactin receptor protein identification. In addition, the presence of aerobactin receptor protein increased the sensitivity of E. coli strains to phage BF23.
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Beltrán, Sáez Elisa. "Information transmission through a nonlinear molecular signaling system: ErbB as a case study." Doctoral thesis, Universitat Autònoma de Barcelona, 2019. http://hdl.handle.net/10803/667354.
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La capacitat dels éssers vius d’obtenir i processar informació és clau per adaptar-se i sobreviure en l’ambient que els envolta. Les cèl·lules, des de procariotes unicel·lulars fins a organismes multicel·lulars (eucariotes), capten informació de l’entorn mitjançant diversos mecanismes, entre ells a través de receptors de membrana, que fan de canal per a la informació entre l’exterior i l’interior de la cèl·lula. Per tant, aquestos receptors representen un canal de transmissió d’informació a través del qual la informació ambiental pot afectar el comportament cel·lular per adaptar-se a l’ambient.
En aquesta tesi, hem estudiat la transmissió d’informació a través del sistema de receptors ErbB, una família de receptors involucrats en diferents comportaments cel·lulars, com per exemple la proliferació o la migració. Gràcies a l’estudi de malalties complexes -centrem-nos en el càncer- des d’una perspectiva molecular, s’han pogut identificar els receptors de la família ErbB com a factors que causen l’enfermetat: quan els receptors ErbB es troben sobreexpressats (produïts en excés), les cèl·lules deixen d’interpretar correctament la informació extracel·lular i proliferen descontroladament, formant tumors. Per tant, la desregulació dels receptors ErbB està molt lligada al que podriem anomenar malalties de la informació, és a dir, malalties causades per la pèrdua de la capacitat d’obtenir i interpretar informació extracel·lular.
Per tal de quantificar la informació que es transmet a través del sistema ErbB, hem modelitzat matemàticament la dinàmica dels receptors a la membrana mitjançant sistemes d’equacions diferencials ordinàries. Els nostres models incorporen la dimerització (formació d’un complex de dos receptors) entre receptors de diferents tipus. Aquesta interacció és necessària per a l’activació dels receptors i introdueix una no linialitat al sistema. La dimerització i activació són els primers passos en la transducció d’informació a l’interior cel·lular, i vénen seguits de la interacció de proteïnes intracel·lulars amb els receptors actius, que hem modelitzat mitjançant models estocàstics (processos de Poisson). Gràcies a la modelització d’aquestos dos processos hem pogut obtenir una estimació de l’estat intracel·lular en termes probabilístics que ens permet aplicar eines de teoria de la informació per quantificar la transmissió d’informació entre l’exterior i l’interior cel·lular.
Els nostres resultats mostren una disminució en la informació transmesa a través del receptors ErbB quan la quantitat de receptors a la membrana augmenta. Aquesta pèrdua de informació depén de la dinàmica entre receptors, així com de la interacció d’aquestos amb les proteïnes intracel·lulars. En particular, hem estudiat la interacció dels receptors actius amb diferents proteïnes intracel·lulars i hem observat que la tendència que es dóna en les proteïnes a interaccionar amb diferents llocs d’unió dels receptors amb afinitats similars es tradueix en un augment en la sinèrgia entre les diferents proteïnes en quant a la informació que detecten.
La quantificació i anàlisi d’aquestes interaccions i de la transmissió de informació que en resulta és clau per entendre millor els processos de senyalització cel·lular i serà útil en el diseny d’estratègies per tractar les malaties de la informació.The ability of organisms to extract and store information from their surroundings marked a revolution in the history of life and allowed survival and adaptation to the environment. Cells, from prokaryots to eukaryots, use specific receptors inserted in their membranes to detect extracellular molecules that cannot cross into the cell, where cell decisions are taken. Hence, those membrane receptors represent an information channel through which the environmental information can affect cell behavior and adaptation. In this Thesis, we modeled information transmission through the ErbB system, a family of receptors involved in many different cellular behaviors, such as cell proliferation or migration. Thanks to the study of complex diseases - let us think of cancer – from a molecular perspective, the ErbB receptors have been identified as factors causing the disease: when they are overexpressed (produced in excess), cells cease to interpret correctly extracellular information, which results in uncontrolled cell proliferation forming tumors. Therefore, dysregulation of ErbB receptors is at the core of what can be called information diseases, that is, diseases that arise from the loss of the capacity to obtain and interpret extracellular information. With the aim of quantifying the information transmitted through the ErbB system, we modeled the dynamics of membrane receptors by means of systems of ordinary differential equations. Our models considers the dimerization (formation of pairs of receptors) between receptors of differet types. This interaction is necessary for receptor activation and introduces a nonlinearity in the system. Dimerization and activation are the first steps in the signaling cascade, followed by the interaction of intracellular proteins with the active receptors. We modeled these interactions by means of stochastic models (Poisson processes). Thanks to the modeling of these two processes (receptor dynamics and interactions with the intracellular proteins), we obtained an estimation of the intracellular stat in probabilistic terms which has allowed us to use tools from information theory to quantify information transmission between the exterior and the interior of the cell. Our results show a decrease in the information transmitted through the ErbB channel as the amount of ErbB receptors at the membrane increases. We considered different dynamics of the receptors and showed that the loss of information depends on the dynamics of interaction between the receptors, as well as on their interactions with the intracellular signaling machinery. In particular, we studied the interaction of active receptors with several signaling intracellular proteins and showed that the observed tendency of proteins to bind several binding sites with similar affinities translates into an increased synergy between the signaling proteins. All in all, quantifying and analysing these interactions results in a better understanding of the dynamics and information transmission through ErbB and similar molecular systems and it can be used for the design of therapeutic strategies for information diseases.
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Zhang, Gaiping. "Bovine IgG Fc receptors." Thesis, University of Hertfordshire, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.387187.
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Torvinen, Maria. "Adenosine receptor/dopamine receptor interactions : molecular and biochemical aspects /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-298-1/.
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Cordomí, Montoya Arnau. "Molecular dynamics simulations of seven-transmembrane receptors." Doctoral thesis, Universitat Politècnica de Catalunya, 2008. http://hdl.handle.net/10803/6464.
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Seven transmembrane (7-TM) G protein coupled receptors (GPCR) constitute the largest family of integral membrane proteins in eukaryotes with more than 1000 members and encoding more than 2% of the human genome. These proteins play a key role in the transmission and transduction of cellular signals responding to hormones, neurotransmitters, light and other agonists, regulating basic biological processes. Their natural abundance together with their localization in the cell membrane makes them suitable targets for therapeutic intervention. Consequently, GPCR are proteins with enormous pharmacologic interest, representing the targets of about 50% of the currently marketed drugs. The current limitations in the experimental techniques necessary for microscopic studies of the membrane as well as membrane proteins emerged the use of computational methods and specifically molecular dynamics simulations. The lead motif of this thesis is the study of GPCR by means of this technique, with the ultimate goal of developing a methodology that can be generalized to the study of most 7-TM as well as other membrane proteins. Since the bovine rhodopsin was the only protein of the GPCR family with a known threedimensional structure at an atomic level until very recently, most of the effort is centered in the study of this receptor as a model of GPCR.
The scope of this thesis is twofold. On the one hand it addresses the study of the simulation conditions, including the procedure as well as the sampling box to get optimal results, and on the other, the biological implications of the structural and dynamical behavior observed in the simulations. Specifically, regarding the methodological aspects of the work, the bovine rhodopsin has been studied using different treatments of long-range electrostatic interactions and sampling conditions, as well as the effect of sampling the protein embedded in different one-component lipid bilayers. The binding of ions to lipid bilayers in the absence of the protein has also been investigated.
Regarding the biological consequences of the analysis of the MD trajectories, it has been carefully addressed the binding site of retinal and its implications in the process of isomerization after photon uptake, the alteration a group of residues constituting the so-called electrostatic lock between helices TM3 and TM6 in rhodopsin putatively used as common activation mechanism of GPCR, and the structural effects caused by the dimerization based on a recent semi-empirical model. Finally, the specific binding of ions to bacteriorhodopsin has also been studied.
The main conclusion of this thesis is provide support to molecular dynamics as technique capable to provide structural and dynamical informational about membranes and membrane proteins, not currently accessible from experimental methods). Moreover, the use of an explicit lipidic environment is crucial for the study the membrane protein dynamics as well as for the protein-protein and lipidprotein interactions.
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Hodyl, Jozef Andrew Zbigniew, and jozef hodyl@flinders edu au. "Silica Immobilised Metal Ion Activated Molecular Receptors." Flinders University. School of Chemistry, Physics and Earth Sciences, 2008. http://catalogue.flinders.edu.au./local/adt/public/adt-SFU20090301.162335.
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Immobilisation of functional entities, such as, enzymes, onto solid supports, as a means of facilitating their removal from the surrounding environment and subsequent regeneration has been in practice for many decades. This work focuses on the immobilisation and analysis of three-walled (pendant armed), cyclen based receptor complexes immobilised onto a silica surface for the purpose of sequestering aromatic anions from aqueous solution: Si-GPS-[Cd(Trac)](ClO4)2, Si-GPS-[Cd(DiPTrac)](ClO4)2, and Si-GPS-[Cd(TriPTrac)](ClO4)2 were the immobilised receptors used.
Initially, synthesis of a three-walled model receptor, [Cd(TracHP12)](ClO4)2, that is not bound to silica yet mimics the properties of the silica anchored receptor complexes with a hydroxypropyl pendant arm was effected. Aromatic anion binding constant measurements were made on the model receptor using 1H NMR monitored titrations in DMSO-d6 which showed that, in comparison to the first generation four-walled receptors, the removal of one of the pendant arms did not affect the binding capability of the receptor's cavity significantly. It was shown that the binding strength correlated well with the pKa of the particular anion with, for example, p-hydroxybenzoate > m-hydroxybenzoate > o-hydroxybenzoate. The precursor to this receptor was then immobilised onto a silica surface and subjected to metal ion uptake studies to gauge its coordination properties with a number of divalent metal(II) ions: Cd(II), Pb(II), Zn(II), Cu(II) and Ca(II). The three Cd(II) coordinated receptor complexes mentioned above were then subjected to inclusion studies with a number of aromatic anions in aqueous conditions whereupon a reversal of the previously mentioned trend, i.e. o-hydroxybenzoate > m-hydroxybenzoate > p-hydroxybenzoate was observed. This indicated that the presence of water in the system changes the hydrogen bonding mode of the host-guest complexes, and was a major discovery arising from this work.
Books on the topic "Molecular receptors"
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Conn, P. Michael. Receptor Molecular Biology: Receptor Molecular Biology. Burlington: Elsevier, 1995.
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Signals and receptors. Milton Keynes: Open University Press, 1986.
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Reisine, Terry. Molecular biology of neurotransmitter receptors. Amsterdam, Netherlands: Elsevier Science Publishers B.V., 1992.
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Linthicum, D. Scott, and Nadir R. Farid, eds. Anti-Idiotypes, Receptors, and Molecular Mimicry. New York, NY: Springer New York, 1988. http://dx.doi.org/10.1007/978-1-4612-3734-1.
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Burch, Ronald M. Molecular biology and pharmacology of bradykinin receptors. Austin: R.G. Landes, 1993.
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Brann, Mark R., ed. Molecular Biology of G-Protein-Coupled Receptors. Boston, MA: Birkhäuser Boston, 1992. http://dx.doi.org/10.1007/978-1-4684-6772-7.
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Fozard, John R., and Pramod R. Saxena, eds. Serotonin: Molecular Biology, Receptors and Functional Effects. Basel: Birkhäuser Basel, 1991. http://dx.doi.org/10.1007/978-3-0348-7259-1.
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Rumsby, Gill. Molecular endocrinology: Genetic analysis of hormones and their receptors. Oxford: BIOS Scientific, 1997.
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Freedman, Leonard P., ed. Molecular Biology of Steroid and Nuclear Hormone Receptors. Boston, MA: Birkhäuser Boston, 1998. http://dx.doi.org/10.1007/978-1-4612-1764-0.
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Kenakin, Terrence P. Molecular pharmacology: A short course. Cambridge, Mass: Blackwell Science, 1997.
Find full textBook chapters on the topic "Molecular receptors"
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Müller, Judith M., and Roland Schüle. "Sex Steroid Receptors: Androgen Receptor, Estrogen Receptors, Progesterone Receptor." In Encyclopedia of Molecular Pharmacology, 1–7. Cham: Springer International Publishing, 2021. http://dx.doi.org/10.1007/978-3-030-21573-6_163-1.
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Müller, Judith M., and Roland Schüle. "Sex Steroid Receptors: Androgen Receptor, Estrogen Receptors, Progesterone Receptor." In Encyclopedia of Molecular Pharmacology, 1415–21. Cham: Springer International Publishing, 2021. http://dx.doi.org/10.1007/978-3-030-57401-7_163.
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Lolait, Stephen J., James A. Roper, Georgina G. J. Hazell, Yunfei Li, Fiona J. Thomson, and Anne-Marie O'Carroll. "Neuropeptide Receptors." In Molecular Neuroendocrinology, 195–215. Chichester, UK: John Wiley & Sons, Ltd, 2016. http://dx.doi.org/10.1002/9781118760369.ch10.
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Kay, Euan R., and David A. Leigh. "Synthetic Molecular Machines." In Functional Synthetic Receptors, 333–406. Weinheim, FRG: Wiley-VCH Verlag GmbH & Co. KGaA, 2005. http://dx.doi.org/10.1002/352760572x.ch7.
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Mocking, T. A. M., R. Bosma, S. N. Rahman, E. W. E. Verweij, Daniel A. McNaught-Flores, Henry F. Vischer, and Rob Leurs. "Molecular Aspects of Histamine Receptors." In Histamine Receptors, 1–49. Cham: Springer International Publishing, 2016. http://dx.doi.org/10.1007/978-3-319-40308-3_1.
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Pedersen, Steen E. "Molecular Structure, Gating, and Regulation." In Nicotinic Receptors, 17–38. New York, NY: Springer New York, 2014. http://dx.doi.org/10.1007/978-1-4939-1167-7_2.
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Ikemoto, Noriaki. "Intra-Molecular Domain-Domain Interaction." In Ryanodine Receptors, 53–65. Boston, MA: Springer US, 2005. http://dx.doi.org/10.1007/0-387-23188-9_6.
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Murshid, Ayesha, Jimmy Theriault, Jianlin Gong, and Stuart K. Calderwood. "Molecular Chaperone Receptors." In Methods in Molecular Biology, 331–44. New York, NY: Springer New York, 2017. http://dx.doi.org/10.1007/978-1-4939-7477-1_24.
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Lassègue, Bernard, Kathy K. Griendling, and R. Wayne Alexander. "Molecular Biology of Angiotensin II Receptors." In Angiotensin Receptors, 17–48. Boston, MA: Springer US, 1994. http://dx.doi.org/10.1007/978-1-4615-2464-9_2.
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Rudkevich, Dmitry M. "Molecular Containers in Action." In Functional Synthetic Receptors, 257–98. Weinheim, FRG: Wiley-VCH Verlag GmbH & Co. KGaA, 2005. http://dx.doi.org/10.1002/352760572x.ch5.
Full textConference papers on the topic "Molecular receptors"
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Batista, Victor de Sousa, Lourival Rodrigues de Sousa Neto, Roberto Ribeiro Faria, Keli Cristina Barbosa dos Reis, and Nailton Monteiro do Nascimento Júnior. "Post-processing of docking results through docking-based comparative intermolecular contacts analysis (dbCICA) of the α4β2 and α7 nicotinic acetylcholine receptors (nAChRs)." In VIII Simpósio de Estrutura Eletrônica e Dinâmica Molecular. Universidade de Brasília, 2020. http://dx.doi.org/10.21826/viiiseedmol2020146.
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The nAChRs are pentameric ligand-gated ionic channels that respond to the endogenous neurotransmitter acetylcholine, with the α4β2 and α7 subtypes being highly expressed in human brain. Those receptors are involved in many neurologic disorders such as Alzheimer’s disease and Schizophrenia, as well as in nicotine addiction. In this context, molecular modelling is a powerful tool for designing novel ligands targeting those receptors. In the present work, we applied dbCICA1 to identify optimal docking conditions for these two receptors. The methodology and results are summarized bellow. Briefly, bioactive compounds acting on each receptor where docked into the crystal structures obtained from PDB (5KXI2 for α4β2 and 5AFH3 for α7) using GOLD4 and the results were post-processed through dbCICA, a genetic algorithm based approach.
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Zhu, Cheng, and Scott E. Chesla. "Dissociation of Individual Molecular Bonds Under Force." In ASME 1997 International Mechanical Engineering Congress and Exposition. American Society of Mechanical Engineers, 1997. http://dx.doi.org/10.1115/imece1997-0286.
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Abstract Specific interactions between receptors on cell surfaces are essential for living organisms to sense and adapt to their environment. For example, CD16A (Feγ receptor IIIA) signals a variety of immune functions upon binding of immunoglobulin (Ig) G. While receptor-ligand binding has been extensively studied in chemical terms, only until very recently has direct measurement of individual bond forces become possible. Evans et al. [1] pioneered the use of the micropipet technique to measure detachment forces between two red blood cells (RBC) crosslinked by antibodies. While these authors achieved the sensitivity necessary to detect individual bonds (in piconewton range), the forces they measured appeared to be those of uprooting the molecules from the cell membrane (cohesive detachment mode) instead of dissociating the antibody-antigen bonds (adhesive detachment mode).
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Simone, E. R., T. A. Davies, N. A. Zabe, S. M. Greenberg-seperaky, and N. E. Larsen. "EARLY PLATELET-THROMBIN RECEPTORS AND THEIR FUNCTIONS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643730.
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Human platelets possess less than 1000 high affinity [Kd=10-9]and 50-100,000 receptors of lower [Kd=10-7] affinity for o(α-thrombin. The selective derivatization of thrombin with the bifunctional crosslinking agent, DNCO, has enabled us to identify these receptorsvia covalent binding of either active siteinhibited tosyllyslmethylketothrombin (TLCK-T) or active Ctf-thrombin (T).Kinetic studies of the inhibition of the platelet-thrombin response by covalently and noncovalently bound TLCK-T have helped to elucidate the roles of the high and low affinity thrombin receptors. The activation parameters examined were initial membrane depolarization, cytoplasmic alkalinization,dense granule secretion of serotonin and lysosomal secretion of β-glucuronidase.Isolation and characterization of the thrombin receptors after covalent photocoupling of the TLCK-T or active T- were performed after solubilization by gel filtration. The intact, high affinity receptor moiety, a glycoprotein, has an approximate molecular weight of∽lSO.OOO daltons; occasionally this protein is found as a dimer of ∽360,000 daltons. When exposed to o(α-T the receptor undergoes proteolysis, leaving a protein of∽80,000 daltons and releasing the remaining glycoprotein into the medium.Higher doses of active T have been shown to bind with lower affinity to a larger protein of approximate molecular weight 600,000 daltons anda smaller protein of 46,000 daltons. Both proteins are nonsusceptible to thrombin proteolysis. Reduction and alkylation of the600,000 dalton complex yielded two and possibly three high molecular weight components (200,000, 160,000, and possibly 145,000daltons) which may correspond to previously suggested GP-Ia and GP-Ib of the GP-I complex. Under different solubilization conditions, two other membrane proteins have been found to be part of the GP-I complex; one which is not a glycoprotein, GP-Ic, while the other is associated with the glycocalyx and is called glycocalicin. Glycocalicin and GP-Icdo inhibit thrombin binding,implying that the low affinity receptor is indeed the previously suggested GP-I complex and does not appear to be directly involved withplatelet activation.Examination of the effect of dose and duration of incubation with non-covalently binding TLCK-T on subsequent α-thrombin response suggests the existence of positive cooperativity among thrombin receptors.Although TLCK-T has the same affinity for platelets (Kd) as T , the rateof binding and therefore that of dissociation are lower. Thus for incubation times of 1 minute or less with up to a 2x saturating TLCK-T dose, the subsequent depolarization response to a saturating T dose was enhanced. Exposure to higher TLCK-T (5x saturating)doses led to significant inhibition.Verification of the potentiation observed in noncovalent TLCK-T studies was performed using TLCK-T covalently bound to the platelet receptor with DNCO. Several hundred thrombin molecules were bound to the platelet when a subsaturating dose of TLCK-T(0.0025 U/ml) was used to crosslink, whileseveral thousand resulted with a saturating (0.05 U/ml) TLCK-T dose. Positive cooperativity was observed with low αT doses (0.005 U/ml) when several hundred high affinity receptors are blocked. The parameters studied which exhibited this positive cooperativity were depolarization, pH change and serotonin secretion, α-Glucuronidase secretion was normal. The presence and degreeof enhancement were donor-variableand suggest different threshhold thrombin dose requirements. The enhancement observed can be attributed to either an increased rate of binding (increased affinity) or to an increased number of exposed binding sites. Since little difference was found between the number of TLCK-T molecules bound after30 versus 60 seconds, we conclude that thepotentiation is more likely due to an increased number of exposed binding sites. Results from covalent crosslinks using a fluorescein and rhodamine labeled-TLCK-T and the fluorescence activated cellsorter support this hypothesis. The sensitization of the high affinity binding sitesby partial occupancy implies these bindingsites are responsible for depolarization, pH change and dense granule secretion (the rapid initial activation response), while βglucuronidase secretion, a secondary response, is otherwise controlled.
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Einolghozati, Arash, Mohsen Sardari, and Faramarz Fekri. "Capacity of diffusion-based molecular communication with ligand receptors." In 2011 IEEE Information Theory Workshop (ITW). IEEE, 2011. http://dx.doi.org/10.1109/itw.2011.6089591.
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Wu, Chunsheng, Liping Du, Ping Wang, and Luhang Zhao. "Olfactory receptors molecular sensors using surface acoustic wave chip." In 2011 IEEE International Conference on Nano/Micro Engineered and Molecular Systems (NEMS). IEEE, 2011. http://dx.doi.org/10.1109/nems.2011.6017571.
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Einolghozati, Arash, and Faramarz Fekri. "Rate-distortion in molecular signal sensing with ligand receptors." In 2015 IEEE International Symposium on Information Theory (ISIT). IEEE, 2015. http://dx.doi.org/10.1109/isit.2015.7282672.
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Geronymo, Beatriz Baaklini, Filomena Marino Carvalho, Adriana Akemi Yoshimura, Juliana Zabukas de Andrade, Danúbia Ariana de Andrade, and Alfredo Carlos Simões Dornellas de Barros. "CORRELATION BETWEEN THE PRESENCE OF ANDROGENIC RECEPTORS AND MOLECULAR AND HISTOPATHOLOGICAL VARIABLES IN BREAST CANCER." In Scientifc papers of XXIII Brazilian Breast Congress - 2021. Mastology, 2021. http://dx.doi.org/10.29289/259453942021v31s1061.
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Introduction: The expression of androgenic receptors (AR) is a new predictive marker of response and prognosis in invasive breast carcinoma (BC). It emerges as a potential therapeutic target. Objectives: To evaluate the frequency of AR positivity and its correlation with molecular and histopathological parameters in infiltrative BC. Methods: Retrospective cohort study, analyzing 119 cases of non-metastatic invasive BC, seen at a private clinic. Hormonal receptors were screened by immunohistochemical reaction, and AR were considered positive when present in at least 10% of cells, ER and PR from 1%. This finding was correlated with pathological staging, histological grade (HG), vascular-lymphatic invasion (VLI), estrogen receptors (ER), progesterone receptors (PR), HER2 and Ki 67. Results: AR were positive in 96 cases (80.6%). The correlation with the surveyed parameters can be seen in the table. Conclusions: AR positivity is associated with more differentiated hormone-dependent tumors and with a lower proliferation rate.
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LAZEBNY, O. E., I. V. LAZEBNAYA, and O. A. KOKSHAROVA. "PHYLOGENETIC ANALYSIS OF CYANOBACTERIAL GLUTAMATE-LIKE RECEPTORS: THE FIRST OVERLOOK." In 5TH MOSCOW INTERNATIONAL CONFERENCE "MOLECULAR PHYLOGENETICSAND BIODIVERSITY BIOBANKING". TORUS PRESS, 2018. http://dx.doi.org/10.30826/molphy2018-53.
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Crow, Matthew J., Kevin Seekell, Stella Marinakos, Julie Ostrander, Ashutosh Chilkoti, and Adam P. Wax. "Hyperspectral molecular imaging of multiple receptors using immunolabeled plasmonic nanoparticles." In SPIE BiOS, edited by Tuan Vo-Dinh and Joseph R. Lakowicz. SPIE, 2011. http://dx.doi.org/10.1117/12.874093.
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ZHANG, YONG, YA-CHUN LEI, and DIAN-SHENG LIU. "MOLECULAR RECOGNITION OF AMINO ACIDS BY HEMATOPORPHYRIN AND METALLOHEMATOPORPHYRIN RECEPTORS." In Proceedings of the 15th International Symposium. WORLD SCIENTIFIC, 2008. http://dx.doi.org/10.1142/9789812839589_0106.
Full textReports on the topic "Molecular receptors"
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Rafaeli, Ada, and Russell Jurenka. Molecular Characterization of PBAN G-protein Coupled Receptors in Moth Pest Species: Design of Antagonists. United States Department of Agriculture, December 2012. http://dx.doi.org/10.32747/2012.7593390.bard.
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The proposed research was directed at determining the activation/binding domains and gene regulation of the PBAN-R’s thereby providing information for the design and screening of potential PBAN-R-blockers and to indicate possible ways of preventing the process from proceeding to its completion. Our specific aims included: (1) The identification of the PBAN-R binding domain by a combination of: (a) in silico modeling studies for identifying specific amino-acid side chains that are likely to be involved in binding PBAN with the receptor and; (b) bioassays to verify the modeling studies using mutant receptors, cell lines and pheromone glands (at tissue and organism levels) against selected, designed compounds to confirm if compounds are agonists or antagonists. (2) The elucidation ofthemolecular regulationmechanisms of PBAN-R by:(a) age-dependence of gene expression; (b) the effect of hormones and; (c) PBAN-R characterization in male hair-pencil complexes. Background to the topic Insects have several closely related G protein-coupled receptors (GPCRs) belonging to the pyrokinin/PBAN family, one with the ligand pheromone biosynthesis activating neuropeptide or pyrokinin-2 and another with diapause hormone or pyrokinin-1 as a ligand. We were unable to identify the diapause hormone receptor from Helicoverpa zea despite considerable effort. A third, related receptor is activated by a product of the capa gene, periviscerokinins. The pyrokinin/PBAN family of GPCRs and their ligands has been identified in various insects, such as Drosophila, several moth species, mosquitoes, Triboliumcastaneum, Apis mellifera, Nasoniavitripennis, and Acyrthosiphon pisum. Physiological functions of pyrokinin peptides include muscle contraction, whereas PBAN regulates pheromone production in moths plus other functions indicating the pleiotropic nature of these ligands. Based on the alignment of annotated genomic sequences, the primary and secondary structures of the pyrokinin/PBAN family of receptors have similarity with the corresponding structures of the capa or periviscerokinin receptors of insects and the neuromedin U receptors found in vertebrates. Major conclusions, solutions, achievements Evolutionary trace analysisof receptor extracellular domains exhibited several class-specific amino acid residues, which could indicate putative domains for activation of these receptors by ligand recognition and binding. Through site-directed point mutations, the 3rd extracellular domain of PBAN-R was shown to be critical for ligand selection. We identified three receptors that belong to the PBAN family of GPCRs and a partial sequence for the periviscerokinin receptor from the European corn borer, Ostrinianubilalis. Functional expression studies confirmed that only the C-variant of the PBAN-R is active. We identified a non-peptide agonist that will activate the PBAN-receptor from H. zea. We determined that there is transcriptional control of the PBAN-R in two moth species during the development of the pupa to adult, and we demonstrated that this transcriptional regulation is independent of juvenile hormone biosynthesis. This transcriptional control also occurs in male hair-pencil gland complexes of both moth species indicating a regulatory role for PBAN in males. Ultimate confirmation for PBAN's function in the male tissue was revealed through knockdown of the PBAN-R using RNAi-mediated gene-silencing. Implications, both scientific and agricultural The identification of a non-peptide agonist can be exploited in the future for the design of additional compounds that will activate the receptor and to elucidate the binding properties of this receptor. The increase in expression levels of the PBAN-R transcript was delineated to occur at a critical period of 5 hours post-eclosion and its regulation can now be studied. The mysterious role of PBAN in the males was elucidated by using a combination of physiological, biochemical and molecular genetics techniques.
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Sasaki, D. Y., T. M. Alam, and R. A. Assink. Synthetic molecular receptors for phosphates and phosphonates in sol-gel materials. Office of Scientific and Technical Information (OSTI), December 1997. http://dx.doi.org/10.2172/563827.
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Rafaeli, Ada, Russell Jurenka, and Chris Sander. Molecular characterisation of PBAN-receptors: a basis for the development and screening of antagonists against Pheromone biosynthesis in moth pest species. United States Department of Agriculture, January 2008. http://dx.doi.org/10.32747/2008.7695862.bard.
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The original objectives of the approved proposal included: (a) The determination of species- and tissue-specificity of the PBAN-R; (b) the elucidation of the role of juvenile hormone in gene regulation of the PBAN-R; (c) the identificationof the ligand binding domains in the PBAN-R and (d) the development of efficient screening assays in order to screen potential antagonists that will block the PBAN-R. Background to the topic: Moths constitute one of the major groups of pest insects in agriculture and their reproductive behavior is dependent on chemical communication. Sex-pheromone blends are utilised by a variety of moth species to attract conspecific mates. In most of the moth species sex-pheromone biosynthesis is under circadian control by the neurohormone, PBAN (pheromone-biosynthesis-activating neuropeptide). In order to devise ideal strategies for mating disruption/prevention, we proposed to study the interactions between PBAN and its membrane-bound receptor in order to devise potential antagonists. Major conclusions: Within the framework of the planned objectives we have confirmed the similarities between the two Helicoverpa species: armigera and zea. Receptor sequences of the two Helicoverpa spp. are 98% identical with most changes taking place in the C-terminal. Our findings indicate that PBAN or PBAN-like receptors are also present in the neural tissues and may represent a neurotransmitter-like function for PBAN-like peptides. Surprisingly the gene encoding the PBAN-receptor was also present in the male homologous tissue, but it is absent at the protein level. The presence of the receptor (at the gene- and protein-levels), and the subsequent pheromonotropic activity are age-dependent and up-regulated by Juvenile Hormone in pharate females but down-regulated by Juvenile Hormone in adult females. Lower levels of pheromonotropic activity were observed when challenged with pyrokinin-like peptides than with HezPBAN as ligand. A model of the 3D structure of the receptor was created using the X-ray structure of rhodopsin as a template after sequence alignment of the HezPBAN-R with several other GPCRs and computer simulated docking with the model predicted putative binding sites. Using in silico mutagenesis the predicted docking model was validated with experimental data obtained from expressed chimera receptors in Sf9 cells created by exchanging between the three extracellular loops of the HezPBAN-R and the Drosophila Pyrokinin-R (CG9918). The chimera receptors also indicated that the 3ʳᵈ extracellular loop is important for recognition of PBAN or Diapause hormone ligands. Implications: The project has successfully completed all the objectives and we are now in a position to be able to design and screen potential antagonists for pheromone production. The successful docking simulation-experiments encourage the use of in silico experiments for initial (high-throughput) screening of potential antagonists. However, the differential responses between the expressed receptor (Sf9 cells) and the endogenous receptor (pheromone glands) emphasize the importance of assaying lead compounds using several alternative bioassays (at the cellular, tissue and organism levels). The surprising discovery of the presence of the gene encoding the PBAN-R in the male homologous tissue, but its absence at the protein level, launches opportunities for studying molecular regulation pathways and the evolution of these GPCRs. Overall this research will advance research towards the goal of finding antagonists for this important class of receptors that might encompass a variety of essential insect functions.
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Sessa, Guido, and Gregory Martin. role of FLS3 and BSK830 in pattern-triggered immunity in tomato. United States Department of Agriculture, January 2016. http://dx.doi.org/10.32747/2016.7604270.bard.
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Pattern-recognition receptors (PRRs) located on the plant cell surface initiate immune responses by perceiving conserved pathogen molecules known as pathogen-associated molecular patterns (PAMPs). PRRs typically function in multiprotein complexes that include transmembrane and cytoplasmickinases and contribute to the initiation and signaling of pattern-triggered immunity (PTI). An important challenge is to identify molecular components of PRR complexes and downstream signaling pathways, and to understand the molecular mechanisms that mediate their function. In research activities supported by BARD-4931, we studied the role of the FLAGELLIN SENSING 3 (FLS3) PRR in the response of tomato leaves to flagellin-derivedPAMPs and PTI. In addition, we investigated molecular properties of the tomato brassinosteroid signaling kinase 830 (BSK830) that physically interacts with FLS3 and is a candidate for acting in the FLS3 signaling pathway. Our investigation refers to the proposal original objectives that were to: 1) Investigate the role of FLS3 and its interacting proteins in PTI; 2) Investigate the role of BSK830 in PTI; 3) Examine molecular and phosphorylation dynamics of the FLS3-BSK830 interaction; 4) Examine the possible interaction of FLS3 and BSK830 with Pstand Xcveffectors. We used CRISPR/Cas9 techniques to develop plants carrying single or combined mutations in the FLS3 gene and in the paralogsFLS2.1 and FLS2.2 genes, which encode the receptor FLAGELLIN SENSING2 (FLS2), and analyzed their function in PTI. Domain swapping analysis of the FLS2 and FLS3 receptors revealed domains of the proteins responsible for PAMP detection and for the different ROS response initiated by flgII-28/FLS3 as compared to flg22/FLS2. In addition, in vitro kinase assays and point mutations analysis identified FLS2 and FLS3 domains required for kinase activity and ATP binding. In research activities on tomato BSK830, we found that it interacts with PRRs and with the co-receptor SERK3A and PAMP treatment affects part of these interactions. CRISPR/Cas9 bsk830 mutant plants displayed enhanced pathogen susceptibility and reduced ROS production upon PAMP treatment. In addition, BSK830 interacted with 8 Xanthomonastype III secreted effectors. Follow up analysis revealed that among these effectors XopAE is part of an operon, is translocated into plant cells, and displays E3 ubiquitinligase activity. Our investigation was also extended to other Arabidopsis and tomato BSK family members. Arabidopsis BSK5 localized to the plant cell periphery, interacted with receptor-like kinases, and it was phosphorylatedin vitro by the PEPR1 and EFRPRRs. bsk5 mutant plants displayed enhanced susceptibility to pathogens and were impaired in several, but not all, PAMP-induced responses. Conversely, BSK5 overexpression conferred enhanced disease resistance and caused stronger PTI responses. Genetic complementation suggested that proper localization, kinase activity, and phosphorylation by PRRs are critical for BSK5 function. BSK7 and BSK8 specifically interacted with the FLS2 PRR, their respective mutant plants were more susceptible to B. cinereaand displayed reduced flg22-induced responses. The tomato BSK Mai1 was found to interact with the M3KMAPKKK, which is involved in activation of cell death associated with effector-triggered immunity. Silencing of Mai1 in N. benthamianaplants compromised cell death induced by a specific class of immune receptors. In addition, co-expression of Mai1 and M3Kin leaves enhanced MAPKphosphorylation and cell death, suggesting that Mai1 acts as a molecular link between pathogen recognition and MAPK signaling. Finally, We identified the PP2C phosphatase Pic1 that acts as a negative regulator of PTI by interacting with and dephosphorylating the receptor-like cytoplasmickinase Pti1, which is a positive regulator of plant immunity. The results of this investigation shed new light on the molecular characteristics and interactions of components of the immune system of crop plants providing new knowledge and tools for development of novel strategies for disease control.
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Altstein, Miriam, and Ronald J. Nachman. Rational Design of Insect Control Agent Prototypes Based on Pyrokinin/PBAN Neuropeptide Antagonists. United States Department of Agriculture, August 2013. http://dx.doi.org/10.32747/2013.7593398.bard.
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The general objective of this study was to develop rationally designed mimetic antagonists (and agonists) of the PK/PBAN Np class with enhanced bio-stability and bioavailability as prototypes for effective and environmentally friendly pest insect management agents. The PK/PBAN family is a multifunctional group of Nps that mediates key functions in insects (sex pheromone biosynthesis, cuticular melanization, myotropic activity, diapause and pupal development) and is, therefore, of high scientific and applied interest. The objectives of the current study were: (i) to identify an antagonist biophores (ii) to develop an arsenal of amphiphilic topically active PK/PBAN antagonists with an array of different time-release profiles based on the previously developed prototype analog; (iii) to develop rationally designed non-peptide SMLs based on the antagonist biophore determined in (i) and evaluate them in cloned receptor microplate binding assays and by pheromonotropic, melanotropic and pupariation in vivo assays. (iv) to clone PK/PBAN receptors (PK/PBAN-Rs) for further understanding of receptor-ligand interactions; (v) to develop microplate binding assays for screening the above SMLs. In the course of the granting period A series of amphiphilic PK/PBAN analogs based on a linear lead antagonist from the previous BARD grant was synthesized that incorporated a diverse array of hydrophobic groups (HR-Suc-A[dF]PRLa). Others were synthesized via the attachment of polyethylene glycol (PEG) polymers. A hydrophobic, biostablePK/PBAN/DH analog DH-2Abf-K prevented the onset of the protective state of diapause in H. zea pupae [EC50=7 pmol/larva] following injection into the preceding larval stage. It effectively induces the crop pest to commit a form of ‘ecological suicide’. Evaluation of a set of amphiphilic PK analogs with a diverse array of hydrophobic groups of the formula HR-Suc-FTPRLa led to the identification of analog T-63 (HR=Decyl) that increased the extent of diapause termination by a factor of 70% when applied topically to newly emerged pupae. Another biostablePK analog PK-Oic-1 featured anti-feedant and aphicidal properties that matched the potency of some commercial aphicides. Native PK showed no significant activity. The aphicidal effects were blocked by a new PEGylated PK antagonist analog PK-dF-PEG4, suggesting that the activity is mediated by a PK/PBAN receptor and therefore indicative of a novel and selective mode-of-action. Using a novel transPro mimetic motif (dihydroimidazole; ‘Jones’) developed in previous BARD-sponsored work, the first antagonist for the diapause hormone (DH), DH-Jo, was developed and shown to block over 50% of H. zea pupal diapause termination activity of native DH. This novel antagonist development strategy may be applicable to other invertebrate and vertebrate hormones that feature a transPro in the active core. The research identifies a critical component of the antagonist biophore for this PK/PBAN receptor subtype, i.e. a trans-oriented Pro. Additional work led to the molecular cloning and functional characterization of the DH receptor from H. zea, allowing for the discovery of three other DH antagonist analogs: Drosophila ETH, a β-AA analog, and a dF analog. The receptor experiments identified an agonist (DH-2Abf-dA) with a maximal response greater than native DH. ‘Deconvolution’ of a rationally-designed nonpeptide heterocyclic combinatorial library with a cyclic bis-guanidino (BG) scaffold led to discovery of several members that elicited activity in a pupariation acceleration assay, and one that also showed activity in an H. zea diapause termination assay, eliciting a maximal response of 90%. Molecular cloning and functional characterization of a CAP2b antidiuretic receptor from the kissing bug (R. prolixus) as well as the first CAP2b and PK receptors from a tick was also achieved. Notably, the PK/PBAN-like receptor from the cattle fever tick is unique among known PK/PBAN and CAP2b receptors in that it can interact with both ligand types, providing further evidence for an evolutionary relationship between these two NP families. In the course of the granting period we also managed to clone the PK/PBAN-R of H. peltigera, to express it and the S. littoralis-R Sf-9 cells and to evaluate their interaction with a variety of PK/PBAN ligands. In addition, three functional microplate assays in a HTS format have been developed: a cell-membrane competitive ligand binding assay; a Ca flux assay and a whole cell cAMP ELISA. The Ca flux assay has been used for receptor characterization due to its extremely high sensitivity. Computer homology studies were carried out to predict both receptor’s SAR and based on this analysis 8 mutants have been generated. The bioavailability of small linear antagonistic peptides has been evaluated and was found to be highly effective as sex pheromone biosynthesis inhibitors. The activity of 11 new amphiphilic analogs has also been evaluated. Unfortunately, due to a problem with the Heliothis moth colony we were unable to select those with pheromonotropic antagonistic activity and further check their bioavailability. Six peptides exhibited some melanotropic antagonistic activity but due to the low inhibitory effect the peptides were not further tested for bioavailability in S. littoralis larvae. Despite the fact that no new antagonistic peptides were discovered in the course of this granting period the results contribute to a better understanding of the interaction of the PK/PBAN family of Nps with their receptors, provided several HT assays for screening of libraries of various origin for presence of PK/PBAN-Ragonists and antagonists and provided important practical information for the further design of new, peptide-based insecticide prototypes aimed at the disruption of key neuroendocrine physiological functions in pest insects.
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Gurevitz, Michael, William A. Catterall, and Dalia Gordon. Learning from Nature How to Design Anti-insect Selective Pesticides - Clarification of the Interacting Face between Insecticidal Toxins and their Na-channel Receptors. United States Department of Agriculture, January 2010. http://dx.doi.org/10.32747/2010.7697101.bard.
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Structural details on the interacting faces of toxins and sodium channels (Navs), and particularly identification of elements that confer specificity for insects, are difficult to approach and require suitable experimental systems. Therefore, natural toxins capable of differential recognition of insect and mammalian Navs are valuable leads for design of selective compounds in insect control. We have characterized several scorpion toxins that vary in preference for insect and mammalian Navs, and identified residues important for their action. However, despite many efforts worldwide, only little is known about the receptor sites of these toxins, and particularly on differences between these sites on insect and mammalian Navs. Another problem arises from the massive overuse of chemical insecticides, which increases resistance buildup among various insect pests. A possible solution to this problem is to combine different insecticidal compounds, especially those that provide synergic effects. Our recent finding that combinations of insecticidal receptor site-3 toxins (sea anemone and scorpion alpha) with scorpion beta toxins or their truncated derivatives are synergic in toxicity to insects is therefore timely and strongly supports this approach. Our ability to produce toxins and various Navs in recombinant forms, enable thorough analysis and structural manipulations of both toxins and receptors. On this basis we propose to (1) restrict by mutagenesis the activity of insecticidal scorpion -toxins and sea anemone toxins to insects, and clarify the molecular basis of their synergic toxicity with antiinsect selective -toxins; (2) identify Nav elements that interact with scorpion alpha and sea anemone toxins and those that determine toxin selectivity to insects; (3) determine toxin-channel pairwise side-chain interactions by thermodynamic mutant cycle analysis using our large collection of mutant -toxins and Nav mutants identified in aim 2; (4) clarify the mode of interaction of truncated -toxins with insect Navs, and elucidate how they enhance the activity of insecticidal site-3 toxins. This research may lead to rational design of novel anti-insect peptidomimetics with minimal impact on human health and the environment, and will establish the grounds for a new strategy in insect pest control, whereby a combination of allosterically interacting compounds increase insecticidal action and reduce risks of resistance buildup.
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Sessa, Guido, and Gregory B. Martin. molecular link from PAMP perception to a MAPK cascade associated with tomato disease resistance. United States Department of Agriculture, January 2012. http://dx.doi.org/10.32747/2012.7597918.bard.
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The research problem: The detection of pathogen-associated molecular patterns (PAMPs) by plant pattern recognition receptors (PRRs) is a key mechanism by which plants activate an effective immune response against pathogen attack. MAPK cascades are important signaling components downstream of PRRs that transduce the PAMP signal to activate various defense responses. Preliminary experiments suggested that the receptor-like cytoplasmickinase (RLCK) Mai5 plays a positive role in pattern-triggered immunity (PTI) and interacts with the MAPKKK M3Kε. We thus hypothesized that Mai5, as other RLCKs, functions as a component PRR complexes and acts as a molecular link between PAMP perception and activation of MAPK cascades. Original goals: The central goal of this research was to investigate the molecular mechanisms by which Mai5 and M3Kε regulate plant immunity. Specific objectives were to: 1. Determine the spectrum of PAMPs whose perception is transmitted by M3Kε; 2. Identify plant proteins that act downstream of M3Kε to mediate PTI; 3. Investigate how and where Mai5 interacts with M3Kε in the plant cell; 4. Examine the mechanism by which Mai5 contributes to PTI. Changes in research directions: We did not find convincing evidence for the involvement of M3Kε in PTI signaling and substituted objectives 1 and 3 with research activities aimed at the analysis of transcriptomic profiles of tomato plants during the onset of plant immunity, isolation of the novel tomato PRR FLS3, and investigation of the involvement of the RLCKBSKs in PTI. Main achievements during this research program are in the following major areas: 1. Functional characterization of Mai5. The function of Mai5 in PTI signaling was demonstrated by testing the effect of silencing the Mai5 gene by virus-induced gene silencing (VIGS) experiments and in cell death assays. Domains of Mai5 that interact with MAPKKKs and subcellular localization of Mai5 were analyzed in detail. 2. Analysis of transcriptional profiles during the tomato immune responses to Pseudomonas syringae (Pombo et al., 2014). We identified tomato genes whose expression is induced specifically in PTI or in effector-triggered immunity (ETI). Thirty ETI-specific genes were examined by VIGS for their involvement in immunity and the MAPKKK EPK1, was found to be required for ETI. 3. Dissection of MAP kinase cascades downstream of M3Kε (Oh et al., 2013; Teper et al., 2015). We identified genes that encode positive (SGT and EDS1) and negative (WRKY1 and WRKY2) regulators of the ETI-associated cell death mediated by M3Kε. In addition, the MKK2 MAPKK, which acts downstream of M3Kε, was found to interact with the MPK3 MAPK and specific MPK3 amino acids involved interaction were identified and found to be required for induction of cell death. We also identified 5 type III effectors of the bacterial pathogen Xanthomonaseuvesicatoria that inhibited cell death induced by components of ETI-associated MAP kinase cascades. 4. Isolation of the tomato PRR FLS3 (Hind et al., submitted). FLS3, a novel PRR of the LRR-RLK family that specifically recognizes the flagellinepitope flgII-28 was isolated. FLS3 was shown to bind flgII-28, to require kinase activity for function, to act in concert with BAK1, and to enhance disease resistance to Pseudomonas syringae. 5. Functional analysis of RLCKs of the brassinosteroid signaling kinase (BSK) family.Arabidopsis and tomato BSKs were found to interact with PRRs. In addition, certain ArabidospsisBSK mutants were found to be impaired in PAMP-induced resistance to Pseudomonas syringae. Scientific and agricultural significance: Our research activities discovered and characterized new molecular components of signaling pathways mediating recognition of invading pathogens and activation of immune responses against them. Increased understanding of molecular mechanisms of immunity will allow them to be manipulated by both molecular breeding and genetic engineering to produce plants with enhanced natural defense against disease.
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Gurevitz, Michael, William A. Catterall, and Dalia Gordon. face of interaction of anti-insect selective toxins with receptor site-3 on voltage-gated sodium channels as a platform for design of novel selective insecticides. United States Department of Agriculture, December 2013. http://dx.doi.org/10.32747/2013.7699857.bard.
Full textAbstract:
Voltage-gated sodium channels (Navs) play a pivotal role in excitability and are a prime target of insecticides like pyrethroids. Yet, these insecticides are non-specific due to conservation of Navs in animals, raising risks to the environment and humans. Moreover, insecticide overuse leads to resistance buildup among insect pests, which increases misuse and risks. This sad reality demands novel, more selective, insect killers whose alternative use would avoid or reduce this pressure. As highly selective insect toxins exist in venomous animals, why not exploit this gift of nature and harness them in insect pest control? Many of these peptide toxins target Navs, and since their direct use via transformed crop plants or mediator microorganisms is problematic in public opinion, we focus on the elucidation of their receptor binding sites with the incentive of raising knowledge for design of toxin peptide mimetics. This approach is preferred nowadays by agro-industries in terms of future production expenses and public concern. However, characterization of a non-continuous epitope, that is the channel receptor binding site for such toxins, requires a suitable experimental system. We have established such a system within more than a decade and reached the stage where we employ a number of different insect-selective toxins for the identification of their receptor sites on Navs. Among these toxins we wish to focus on those that bind at receptor site-3 and inhibit Nav inactivation because: (1) We established efficient experimental systems for production and manipulation of site-3 toxins from scorpions and sea anemones. These peptides vary in size and structure but compete for site-3 on insect Navs. Moreover, these toxins exhibit synergism with pyrethroids and with other channel ligands; (2) We determined their bioactive surfaces towards insect and mammalian receptors (see list of publications); (3) We found that despite the similar mode of action on channel inactivation, the preference of the toxins for insect and mammalian channel subtypes varies greatly, which can direct us to structural features in the basis of selectivity; (4) We have identified by channel loop swapping and point mutagenesis extracellular segments of the Navinvolved with receptor site-3. On this basis and using channel scanning mutagenesis, neurotoxin binding, electrophysiological analyses, and structural data we offer: (i) To identify the residues that form receptor site-3 at insect and mammalian Navs; (ii) To identify by comparative analysis differences at site-3 that dictate selectivity toward various Navs; (iii) To exploit the known toxin structures and bioactive surfaces for modeling their docking at the insect and mammalian channel receptors. The results of this study will enable rational design of novel anti-insect peptide mimetics with minimized risks to human health and to the environment. We anticipate that the release of receptor site-3 molecular details would initiate a worldwide effort to design peptide mimetics for that site. This will establish new strategies in insect pest control using alternative insecticides and the combined use of compounds that interact allosterically leading to increased efficiency and reduced risks to humans or resistance buildup among insect pests.
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DuSell, Carolyn. Molecular Determinants of Estrogen Receptor Alpha Stability. Fort Belvoir, VA: Defense Technical Information Center, July 2008. http://dx.doi.org/10.21236/ada494436.
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DuSell, Carolyn D. Molecular Determinants of Estrogen Receptor Alpha Stability. Fort Belvoir, VA: Defense Technical Information Center, July 2007. http://dx.doi.org/10.21236/ada473731.
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