Journal articles: 'Receptor-ligand complexes'

1

Veeramani, Suresh, and George J. Weiner. "Quantification of Receptor Occupancy by Ligand—An Understudied Class of Potential Biomarkers." Cancers 12, no. 10 (October 13, 2020): 2956. http://dx.doi.org/10.3390/cancers12102956.

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Molecular complexes, such as ligand–receptor complexes, are vital for both health and disease and can be shed into the circulation in soluble form. Relatively little is known about the biology of soluble ligand–receptor complexes. The functional importance of such complexes and their potential use as clinical biomarkers in diagnosis and therapy remains underappreciated. Most traditional technologies used to study ligand–receptor complexes measure the individual levels of soluble ligands or receptors rather than the complexes themselves. The fraction of receptors occupied by ligand, and the potential clinical relevance of such information, has been largely overlooked. Here, we review the biological significance of soluble ligand–receptor complexes with a specific focus on their potential as biomarkers of cancer and other inflammatory diseases. In addition, we discuss a novel RNA aptamer-based technology, designated ligand–receptor complex-binding aptamers (LIRECAP), that can provide precise measurement of the fraction of a soluble receptor occupied by its ligand. The potential applicability of the LIRECAP technology as a biomarker discovery platform is also described.

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Guvench, Olgun, Daniel J. Price, and Charles L. Brooks. "Receptor rigidity and ligand mobility in trypsin-ligand complexes." Proteins: Structure, Function, and Bioinformatics 58, no. 2 (December 1, 2004): 407–17. http://dx.doi.org/10.1002/prot.20326.

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Särndahl, E., M. Lindroth, T. Bengtsson, M. Fällman, J. Gustavsson, O. Stendahl, and T. Andersson. "Association of ligand-receptor complexes with actin filaments in human neutrophils: a possible regulatory role for a G-protein." Journal of Cell Biology 109, no. 6 (December 1, 1989): 2791–99. http://dx.doi.org/10.1083/jcb.109.6.2791.

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Most ligand-receptor interactions result in an immediate generation of various second messengers and a subsequent association of the ligand-receptor complex to the cytoskeleton. Depending on the receptor involved, this linkage to the cytoskeleton has been suggested to play a role in the termination of second messenger generation and/or the endocytic process whereby the ligand-receptor complex is internalized. We have studied how the binding of chemotactic peptide-receptor complexes to the cytoskeleton of human neutrophils is accomplished. As much as 76% of the tritiated formylmethionyl-leucyl-phenylalanine (fMet-Leu-[3H]Phe) specifically bound to intact cells, obtained by a 30-s stimulation with 20 nM fMet-Leu-[3H]Phe, still remained after Triton X-100 extraction. Preincubating intact cells with dihydrocytochalasin B (dhCB) or washing the cytoskeletal preparation with a high concentration of potassium, reduced the binding of ligand-receptor complexes to the cytoskeleton by 46% or more. Inhibition of fMet-Leu-Phe-induced generation of second messengers by ADP-ribosylating the alpha-subunit of the receptor-coupled G-protein with pertussis toxin, did not reduce the binding of ligand-receptor complexes to the cytoskeleton. However, using guanosine-5'-O-(2-thiodiphosphate) (GDP beta S) to prevent the dissociation of the fMet-Leu-Phe-associated G-protein within electrically permeabilized cells, led to a pronounced reduction (62%) of the binding between ligand-receptor complexes and the cytoskeleton. In summary, in human neutrophils the rapid association between chemotactic peptide-receptor complexes and the cytoskeleton is dependent on filamentous actin. This association is most likely regulated by the activation and dissociation of the fMet-Leu-Phe-associated G-protein.

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Suthaus, Jan, Anna Tillmann, Inken Lorenzen, Elena Bulanova, Stefan Rose-John, and Jürgen Scheller. "Forced Homo- and Heterodimerization of All gp130-Type Receptor Complexes Leads to Constitutive Ligand-independent Signaling and Cytokine-independent Growth." Molecular Biology of the Cell 21, no. 15 (August 2010): 2797–807. http://dx.doi.org/10.1091/mbc.e10-03-0240.

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Naturally ligand independent constitutively active gp130 variants were described to be responsible for inflammatory hepatocellular adenomas. Recently, we genetically engineered a ligand-independent constitutively active gp130 variant based on homodimerization of Jun leucine zippers. Because also heterodimeric complexes within the gp130 family may have tumorigenic potential, we seek to generate ligand-independent constitutively active heterodimers for all known gp130-receptor complexes based on IL-15/IL-15Rα-sushi fusion proteins. Ligand-independent heterodimerization of gp130 with WSX-1, LIFR, and OSMR and of OSMR with GPL led to constitutive, ligand-independent STAT1 and/or STAT3 and ERK1/2 phosphorylation. Moreover, these receptor combinations induced transcription of the STAT3 target genes c-myc and Pim-1 and factor-independent growth of stably transduced Ba/F3-gp130 cells. Here, we establish the IL-15/IL-15Rα-sushi system as a new system to mimic constitutive and ligand-independent activation of homo- and heterodimeric receptor complexes, which might be applicable to other heterodimeric receptor families. A mutated IL-15 protein, which was still able to bind the IL-15Rα-sushi domain, but not to β- and γ-receptor chains, in combination with the 2A peptide technology may be used to translate our in vitro data into the in vivo situation to assess the tumorigenic potential of gp130-heterodimeric receptor complexes.

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Czekay, R. P., R. A. Orlando, L. Woodward, M. Lundstrom, and M. G. Farquhar. "Endocytic trafficking of megalin/RAP complexes: dissociation of the complexes in late endosomes." Molecular Biology of the Cell 8, no. 3 (March 1997): 517–32. http://dx.doi.org/10.1091/mbc.8.3.517.

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Megalin (gp330) is a member of the low-density lipoprotein receptor gene family. Like other members of the family, it is an endocytic receptor that binds a number of specific ligands. Megalin also binds the receptor-associated protein (RAP) that serves as an exocytic traffic chaperone and inhibits ligand binding to the receptor. To investigate the fate of megalin/RAP complexes, we bound RAP glutathione-S-transferase fusion protein (RAP-GST) to megalin at the surface of L2 yolk sac carcinoma cells and followed the trafficking of the complexes by immunofluorescence and immunogold labeling and by their distribution on Percoll gradients. We show that megalin/RAP-GST complexes, which are internalized via clathrin-coated pits, are delivered to early endosomes where they accumulate during an 18 degrees C temperature block and colocalize with transferrin and transferrin receptor. Upon release from the temperature block, the complexes travel to late endosomes where they colocalize with rab7 and can be coprecipitated with anti-RAP-GST antibodies. Dissociation of the complex occurs in late endosomes and is most likely triggered by the low pH (approximately 5.5) of this compartment. RAP is then rapidly delivered to lysosomes and degraded whereas megalin is recycled to the cell surface. When the ligand, lipoprotein lipase, was bound to megalin, the receptor was found to recycle through early endosomes. We conclude that in contrast to receptor/ligand complexes, megalin/RAP complexes traffic through late endosomes, which is a novelty for members of the low-density lipoprotein receptor gene family.

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Niu, Linghao, David W. Golde, Juan Carlos Vera, and Mark L. Heaney. "Kinetic Resolution of Two Mechanisms for High-Affinity Granulocyte-Macrophage Colony-Stimulating Factor Binding to Its Receptor." Blood 94, no. 11 (December 1, 1999): 3748–53. http://dx.doi.org/10.1182/blood.v94.11.3748.423k16_3748_3753.

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Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an important hematopoietic cytokine that exerts its effects by interaction with the GM-CSF receptor (GMR) on the surface of responsive cells. The GM-CSF receptor consists of two subunits: GMR, which binds GM-CSF with low affinity, and GMRβ, which lacks intrinsic ligand-binding capability but complexes with GMR to form a high-affinity receptor (GMR/β). We conducted dynamic kinetic analyses of GM-CSF receptors to define the role of GMRβ in the interaction of ligand and receptor. Our data show that GMR/β exhibits a higher kon than GMR, indicating that GMRβ facilitates ligand acquisition to the binding pocket. Heterogeneity with regard to GM-CSF dissociation from GMR/β points to the presence of loose and tight ligand-receptor complexes in high-affinity binding. Although the loose complex has a koff similar to GMR, the lower koffindicates that GMRβ inhibits GM-CSF release from the tight receptor complex. The two rates of ligand dissociation may provide for discrete mechanisms of interaction between GM-CSF and its high-affinity receptor. These results show that the β subunit functions to stabilize ligand binding as well as to facilitate ligand acquisition.

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7

Clark, Kevin P., and Ajay. "Flexible ligand docking without parameter adjustment across four ligand-receptor complexes." Journal of Computational Chemistry 16, no. 10 (October 1995): 1210–26. http://dx.doi.org/10.1002/jcc.540161004.

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8

Meijsing, Sebastiaan H., Cem Elbi, Hans F. Luecke, Gordon L. Hager, and Keith R. Yamamoto. "The Ligand Binding Domain Controls Glucocorticoid Receptor Dynamics Independent of Ligand Release." Molecular and Cellular Biology 27, no. 7 (January 29, 2007): 2442–51. http://dx.doi.org/10.1128/mcb.01570-06.

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ABSTRACT Ligand binding to the glucocorticoid receptor (GR) results in receptor binding to glucocorticoid response elements (GREs) and the formation of transcriptional regulatory complexes. Equally important, these complexes are continuously disassembled, with active processes driving GR off GREs. We found that cochaperone p23-dependent disruption of GR-driven transcription depended on the ligand binding domain (LBD). Next, we examined the importance of the LBD and of ligand dissociation in GR-GRE dissociation in living cells. We showed in fluorescence recovery after photobleaching studies that dissociation of GR from GREs is faster in the absence of the LBD. Furthermore, GR interaction with a target promoter revealed ligand-specific exchange rates. However, using covalently binding ligands, we demonstrated that ligand dissociation is not required for receptor dissociation from GREs. Overall, these studies showed that activities impinging on the LBD regulate GR exchange with GREs but that the dissociation of GR from GREs is independent from ligand dissociation.

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9

Niu, Linghao, David W. Golde, Juan Carlos Vera, and Mark L. Heaney. "Kinetic Resolution of Two Mechanisms for High-Affinity Granulocyte-Macrophage Colony-Stimulating Factor Binding to Its Receptor." Blood 94, no. 11 (December 1, 1999): 3748–53. http://dx.doi.org/10.1182/blood.v94.11.3748.

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Abstract Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an important hematopoietic cytokine that exerts its effects by interaction with the GM-CSF receptor (GMR) on the surface of responsive cells. The GM-CSF receptor consists of two subunits: GMR, which binds GM-CSF with low affinity, and GMRβ, which lacks intrinsic ligand-binding capability but complexes with GMR to form a high-affinity receptor (GMR/β). We conducted dynamic kinetic analyses of GM-CSF receptors to define the role of GMRβ in the interaction of ligand and receptor. Our data show that GMR/β exhibits a higher kon than GMR, indicating that GMRβ facilitates ligand acquisition to the binding pocket. Heterogeneity with regard to GM-CSF dissociation from GMR/β points to the presence of loose and tight ligand-receptor complexes in high-affinity binding. Although the loose complex has a koff similar to GMR, the lower koffindicates that GMRβ inhibits GM-CSF release from the tight receptor complex. The two rates of ligand dissociation may provide for discrete mechanisms of interaction between GM-CSF and its high-affinity receptor. These results show that the β subunit functions to stabilize ligand binding as well as to facilitate ligand acquisition.

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10

Danilowicz, Claudia, Derek Greenfield, and Mara Prentiss. "Dissociation of Ligand−Receptor Complexes Using Magnetic Tweezers." Analytical Chemistry 77, no. 10 (May 2005): 3023–28. http://dx.doi.org/10.1021/ac050057+.

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11

Jones, Stacie M., Susan K. Foreman, Brian B. Shank, and Richard C. Kurten. "EGF receptor downregulation depends on a trafficking motif in the distal tyrosine kinase domain." American Journal of Physiology-Cell Physiology 282, no. 3 (March 1, 2002): C420—C433. http://dx.doi.org/10.1152/ajpcell.00253.2001.

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On binding to its receptor, epidermal growth factor (EGF) initiates a cascade of events leading to cell proliferation or differentiation. In addition, the EGF receptor itself is downregulated to attenuate mitogenic signaling. Downregulation occurs through trafficking of receptors to lysosomes, culminating in proteolytic destruction of both the receptor and ligand; however, endocytic sorting mechanisms that underlie lysosomal targeting remain obscure. The goal of this study was to explore one aspect of the molecular basis for ligand-induced lysosomal targeting and degradation of EGF receptors. In this study, we identify a tyrosine-leucine motif (954YLVI) that is essential for transit of ligand-receptor complexes to lysosomes. When this motif is mutated, HEK 293 cells expressing the mutant receptors demonstrate impaired lysosomal targeting and downregulation compared with wild-type receptors.954YLVI is highly conserved among EGF receptors from various mammalian and invertebrate species and is critical for receptor downregulation. We propose that 954YLVI works in concert with at least two additional regions within the EGF receptor cytoplasmic domain that are essential for efficiently targeting ligand-receptor complexes to the lysosome.

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12

Kumar, Manish, Poonam Jangra Darolia, Nidhi Antil, Mahak Dalal, Jitender Narwal, K. K. Verma, and Sapana Garg. "Spectral, Theoretical and Biological Studies of 3-((4-Mercaptophenyl)imino)- 1-phenylindolin-2-one Schiff Base and Its Organotellurium(IV) Complexes." Asian Journal of Chemistry 33, no. 8 (2021): 1749–56. http://dx.doi.org/10.14233/ajchem.2021.23214.

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Schiff base ligand (3-((4-mercaptophenyl)imino)-1-phenylindolin-2-one) of 1-phenylindoline-2,3-dione and 4-aminothiophenol was synthesized by refluxing. Organotellurium(IV) complexes of type (RTeCl3.NPhIATP and R2TeCl2.NPhIATP, where R = 4-hydroxyphenyl, 4-methoxyphenyl and 3-methyl-4-hydroxyphenyl, NPhIATP = Schiff base ligand). The ligand and its organotellurium(IV) complexes (9a-f) were characterized by FT-IR, molar conductance, elemental analyses, UV-vis, mass, 1H & 13C NMR spectral studies. Geometry of all the compounds were optimized and octahedral geometry have been proposed for all the tellurium(IV) complexes. Molecular docking was studied to find the binding interactions between ligand (NPhIATP) and receptor proteins: E. coli (3t88) and S. aureus (3ty7). The antimicrobial activity of ligand and its tellurium(IV) complexes have been screened against bacteria and fungi. All the organotellurium(IV) complexes complexes showed good activity to ligand towards different studied microorganisms.

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13

Chen, X., Z. L. Ji, D. G. Zhi, and Y. Z. Chen. "CLiBE: a database of computed ligand binding energy for ligand–receptor complexes." Computers & Chemistry 26, no. 6 (November 2002): 661–66. http://dx.doi.org/10.1016/s0097-8485(02)00050-5.

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14

López-García, M., M. Nowicka, C. Bendtsen, G. Lythe, S. Ponnambalam, and C. Molina-París. "Quantifying the phosphorylation timescales of receptor–ligand complexes: a Markovian matrix-analytic approach." Open Biology 8, no. 9 (September 2018): 180126. http://dx.doi.org/10.1098/rsob.180126.

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Cells interact with the extracellular environment by means of receptor molecules on their surface. Receptors can bind different ligands, leading to the formation of receptor–ligand complexes. For a subset of receptors, called receptor tyrosine kinases, binding to ligand enables sequential phosphorylation of intra-cellular residues, which initiates a signalling cascade that regulates cellular function and fate. Most mathematical modelling approaches employed to analyse receptor signalling are deterministic, especially when studying scenarios of high ligand concentration or large receptor numbers. There exist, however, biological scenarios where low copy numbers of ligands and/or receptors need to be considered, or where signalling by a few bound receptor–ligand complexes is enough to initiate a cellular response. Under these conditions stochastic approaches are appropriate, and in fact, different attempts have been made in the literature to measure the timescales of receptor signalling initiation in receptor–ligand systems. However, these approaches have made use of numerical simulations or approximations, such as moment-closure techniques. In this paper, we study, from an analytical perspective, the stochastic times to reach a given signalling threshold for two receptor–ligand models. We identify this time as an extinction time for a conveniently defined auxiliary absorbing continuous time Markov process, since receptor–ligand association/dissociation events can be analysed in terms of quasi-birth-and-death processes. We implement algorithmic techniques to compute the different order moments of this time, as well as the steady-state probability distribution of the system. A novel feature of the approach introduced here is that it allows one to quantify the role played by each kinetic rate in the timescales of signal initiation, and in the steady-state probability distribution of the system. Finally, we illustrate our approach by carrying out numerical studies for the vascular endothelial growth factor and one of its receptors, the vascular endothelial growth factor receptor of human endothelial cells.

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Johnstone, Elizabeth K. M., Heng B. See, Rekhati S. Abhayawardana, Angela Song, K. Johan Rosengren, Stephen J. Hill, and Kevin D. G. Pfleger. "Investigation of Receptor Heteromers Using NanoBRET Ligand Binding." International Journal of Molecular Sciences 22, no. 3 (January 22, 2021): 1082. http://dx.doi.org/10.3390/ijms22031082.

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Receptor heteromerization is the formation of a complex involving at least two different receptors with pharmacology that is distinct from that exhibited by its constituent receptor units. Detection of these complexes and monitoring their pharmacology is crucial for understanding how receptors function. The Receptor-Heteromer Investigation Technology (Receptor-HIT) utilizes ligand-dependent modulation of interactions between receptors and specific biomolecules for the detection and profiling of heteromer complexes. Previously, the interacting biomolecules used in Receptor-HIT assays have been intracellular proteins, however in this study we have for the first time used bioluminescence resonance energy transfer (BRET) with fluorescently-labeled ligands to investigate heteromerization of receptors on the cell surface. Using the Receptor-HIT ligand binding assay with NanoBRET, we have successfully investigated heteromers between the angiotensin II type 1 (AT1) receptor and the β2 adrenergic receptor (AT1-β2AR heteromer), as well as between the AT1 and angiotensin II type 2 receptor (AT1-AT2 heteromer).

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Onufriev, Alexey V., and Emil Alexov. "Protonation and pK changes in protein–ligand binding." Quarterly Reviews of Biophysics 46, no. 2 (May 2013): 181–209. http://dx.doi.org/10.1017/s0033583513000024.

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AbstractFormation of protein–ligand complexes causes various changes in both the receptor and the ligand. This review focuses on changes in pK and protonation states of ionizable groups that accompany protein–ligand binding. Physical origins of these effects are outlined, followed by a brief overview of the computational methods to predict them and the associated corrections to receptor–ligand binding affinities. Statistical prevalence, magnitude and spatial distribution of the pK and protonation state changes in protein–ligand binding are discussed in detail, based on both experimental and theoretical studies. While there is no doubt that these changes occur, they do not occur all the time; the estimated prevalence varies, both between individual complexes and by method. The changes occur not only in the immediate vicinity of the interface but also sometimes far away. When receptor–ligand binding is associated with protonation state change at particular pH, the binding becomes pH dependent: we review the interplay between sub-cellular characteristic pH and optimum pH of receptor–ligand binding. It is pointed out that there is a tendency for protonation state changes upon binding to be minimal at physiologically relevant pH for each complex (no net proton uptake/release), suggesting that native receptor–ligand interactions have evolved to reduce the energy cost associated with ionization changes. As a result, previously reported statistical prevalence of these changes – typically computed at the same pH for all complexes – may be higher than what may be expected at optimum pH specific to each complex. We also discuss whether proper account of protonation state changes appears to improve practical docking and scoring outcomes relevant to structure-based drug design. An overview of some of the existing challenges in the field is provided in conclusion.

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Potemkin, Vladimir, and Maria Grishina. "The Complementarity Principle—One More Step towards Analytical Docking on the Example of Dihydrofolate Reductase Complexes." Life 11, no. 9 (September 19, 2021): 983. http://dx.doi.org/10.3390/life11090983.

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New approaches to assessing the “enzyme–ligand” complementarity, taking into account hydrogens, have been proposed. The approaches are based on the calculation of three-dimensional maps of the electron density of the receptor–ligand complexes. The action of complementarity factors, first proposed in this article, has been demonstrated on complexes of human dihydrofolate reductase (DHFR) with ligands. We found that high complementarity is ensured by the formation of the most effective intermolecular contacts, which are provided due to predominantly paired atomic–atomic interactions, while interactions of the bifurcate and more disoriented type are minimized. An analytical docking algorithm based on the proposed receptor–ligand complementarity factors is proposed.

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Savastano, Matteo, Carlotta Cappanni, Carla Bazzicalupi, Cristiana Lofrumento, and Antonio Bianchi. "Anion Coordination into Ligand Clefts." Crystals 13, no. 5 (May 16, 2023): 823. http://dx.doi.org/10.3390/cryst13050823.

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A tripodal anion receptor has been obtained by an easy and fast single-reaction synthesis from commercial reagents. The three ligand arms-bearing aromatic groups able to form anion–π interactions define ligand clefts where large anions, such as perchlorate and perrhenate, are included. We report here the synthesis of the ligand, its acid/base properties in an aqueous solution which has been used to direct the synthesis of anion complexes, and the crystal structure of the free ligand and its anion complexes H3L(ClO4)2·H2O and H3L(ReO4)2.

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Hohmann, Ulrich, Julia Santiago, Joël Nicolet, Vilde Olsson, Fabio M. Spiga, Ludwig A. Hothorn, Melinka A. Butenko, and Michael Hothorn. "Mechanistic basis for the activation of plant membrane receptor kinases by SERK-family coreceptors." Proceedings of the National Academy of Sciences 115, no. 13 (March 12, 2018): 3488–93. http://dx.doi.org/10.1073/pnas.1714972115.

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Plant-unique membrane receptor kinases with leucine-rich repeat ectodomains (LRR-RKs) can sense small molecule, peptide, and protein ligands. Many LRR-RKs require SERK-family coreceptor kinases for high-affinity ligand binding and receptor activation. How one coreceptor can contribute to the specific binding of distinct ligands and activation of different LRR-RKs is poorly understood. Here we quantitatively analyze the contribution of SERK3 to ligand binding and activation of the brassinosteroid receptor BRI1 and the peptide hormone receptor HAESA. We show that while the isolated receptors sense their respective ligands with drastically different binding affinities, the SERK3 ectodomain binds the ligand-associated receptors with very similar binding kinetics. We identify residues in the SERK3 N-terminal capping domain, which allow for selective steroid and peptide hormone recognition. In contrast, residues in the SERK3 LRR core form a second, constitutive receptor–coreceptor interface. Genetic analyses of protein chimera between BRI1 and SERK3 define that signaling-competent complexes are formed by receptor–coreceptor heteromerization in planta. A functional BRI1–HAESA chimera suggests that the receptor activation mechanism is conserved among different LRR-RKs, and that their signaling specificity is encoded in the kinase domain of the receptor. Our work pinpoints the relative contributions of receptor, ligand, and coreceptor to the formation and activation of SERK-dependent LRR-RK signaling complexes regulating plant growth and development.

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Pokrovskaya, E. "DNA slows dissociation of progesterone receptor–steroid ligand complexes." Steroids 68, no. 4 (April 2003): 351–59. http://dx.doi.org/10.1016/s0039-128x(03)00031-x.

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21

Ganem, Bruce, Yu Tsyr Li, and Jack D. Henion. "Detection of noncovalent receptor-ligand complexes by mass spectrometry." Journal of the American Chemical Society 113, no. 16 (July 1991): 6294–96. http://dx.doi.org/10.1021/ja00016a069.

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Carlsson, Gunilla H., Dirk Hasse, Francesca Cardinale, Cristina Prandi, and Inger Andersson. "The elusive ligand complexes of the DWARF14 strigolactone receptor." Journal of Experimental Botany 69, no. 9 (January 31, 2018): 2345–54. http://dx.doi.org/10.1093/jxb/ery036.

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Klotz, Irving M. "Ligand-Receptor Complexes: Origin and Development of the Concept." Journal of Biological Chemistry 279, no. 1 (November 6, 2003): 1–12. http://dx.doi.org/10.1074/jbc.x300006200.

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Smock, Robert G., and Rob Meijers. "Roles of glycosaminoglycans as regulators of ligand/receptor complexes." Open Biology 8, no. 10 (October 2018): 180026. http://dx.doi.org/10.1098/rsob.180026.

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Glycosaminoglycans (GAGs) play a widespread role in embryonic development, as deletion of enzymes that contribute to GAG synthesis lead to deficiencies in cell migration and tissue modelling. Despite the biochemical and structural characterization of individual protein/GAG interactions, there is no concept available that links the molecular mechanisms of GAG/protein engagements to tissue development. Here, we focus on the role of GAG polymers in mediating interactions between cell surface receptors and their ligands. We categorize several switches that lead to ligand activation, inhibition, selection and addition, based on recent structural studies of select receptor/ligand complexes. Based on these principles, we propose that individual GAG polymers may affect several receptor pathways in parallel, orchestrating a cellular response to an environmental cue. We believe that it is worthwhile to study the role of GAGs as molecular switches, as this may lead to novel drug candidates to target processes such as angiogenesis, neuroregeneration and tumour metastasis.

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de Araujo, Alexandre Suman, Leandro Martínez, Ricardo de Paula Nicoluci, Munir S. Skaf, and Igor Polikarpov. "Structural modeling of high-affinity thyroid receptor–ligand complexes." European Biophysics Journal 39, no. 11 (May 30, 2010): 1523–36. http://dx.doi.org/10.1007/s00249-010-0610-2.

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Alkorta, Ibon, and Gilda H. Loew. "A 3D model of the δ opioid receptor and ligand-receptor complexes." "Protein Engineering, Design and Selection" 9, no. 7 (1996): 573–83. http://dx.doi.org/10.1093/protein/9.7.573.

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Ukkonen, P., V. Lewis, M. Marsh, A. Helenius, and I. Mellman. "Transport of macrophage Fc receptors and Fc receptor-bound ligands to lysosomes." Journal of Experimental Medicine 163, no. 4 (April 1, 1986): 952–71. http://dx.doi.org/10.1084/jem.163.4.952.

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Mouse macrophage Fc receptors specific for IgG1/IgG2b mediate the binding and pinocytic uptake of soluble IgG-containing antibody-antigen complexes. Internalization of these multivalent IgG complexes is accompanied not only by the intracellular degradation of the ligand, but also by a net decrease in the number of plasma membrane Fc receptors and an accelerated rate of receptor turnover. In contrast, internalized receptors bound to a monovalent ligand, the high affinity Fab fragment of the antireceptor mAb 2.4G2, escape degradation by rapidly recycling to the cell surface. In this paper, we have characterized the intracellular pathway involved in the endocytosis and transport of Fc receptors in the J774 macrophage cell line. The results show that the uptake of multivalent ligands follows the normal pathway of receptor-mediated endocytosis: internalization in clathrin-coated pits and coated vesicles, delivery to endosomes, and finally to acid hydrolase-rich lysosomes. Immunoprecipitation of radiolabeled receptor from Percoll density gradients showed that endocytosis of the IgG complexes also results in the concomitant transport of the receptor to lysosomes. Although uptake of the monovalent Fab fragment had no detectable effect on intracellular receptor distribution, preparations of 2.4G2 Fab rendered multivalent by adsorption to colloidal gold were as effective as the IgG complexes at causing lysosomal accumulation of internalized receptors. Thus, it is likely that the down-regulation and degradation of Fc receptors which occurs during the endocytosis of antibody-antigen complexes is due to the transport of internalized receptors to lysosomes. Moreover, the ability of certain Fc receptor-bound ligands to interfere with receptor recycling and trigger lysosomal transport seems to depend on ligand valency rather than on the presence or absence of Fc domains on intact IgG molecules.

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Slusarz, R., R. Kaźmierkiewicz, A. Giełdoń, B. Lammek, and J. Ciarkowski. "Molecular docking-based test for affinities of two ligands toward vasopressin and oxytocin receptors." Acta Biochimica Polonica 48, no. 1 (March 31, 2001): 131–35. http://dx.doi.org/10.18388/abp.2001_5119.

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Molecular docking simulations are now fast developing area of research. In this work we describe an effective procedure of preparation of the receptor-ligand complexes. The amino-acid residues involved in ligand binding were identified and described.

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Fischer, J. A., R. Muff, and W. Born. "Functional relevance of G-protein-coupled-receptor-associated proteins, exemplified by receptor-activity-modifying proteins (RAMPs)." Biochemical Society Transactions 30, no. 4 (August 1, 2002): 455–60. http://dx.doi.org/10.1042/bst0300455.

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The calcitonin (CT) receptor (CTR) and the CTR-like receptor (CRLR) are close relatives within the type II family of G-protein-coupled receptors, demonstrating sequence identity of 50%. Unlike the interaction between CT and CTR, receptors for the related hormones and neuropeptides amylin, CT-gene-related peptide (CGRP) and adrenomedullin (AM) require one of three accessory receptor-activity-modifying proteins (RAMPs) for ligand recognition. An amylin/CGRP receptor is revealed when CTR is co-expressed with RAMP1. When complexed with RAMP3, CTR interacts with amylin alone. CRLR, initially classed as an orphan receptor, is a CGRP receptor when co-expressed with RAMP1. The same receptor is specific for AM in the presence of RAMP2. Together with human RAMP3, CRLR defines an AM receptor, and with mouse RAMP3 it is a low-affinity CGRP/AM receptor. CTR-RAMP1, antagonized preferentially by salmon CT-(8–32) and not by CGRP-(8–37), and CRLR-RAMP1, antagonized by CGRP-(8–37), are two CGRP receptor isotypes. Thus amylin and CGRP interact specifically with heterodimeric complexes between CTR and RAMP1 or RAMP3, and CGRP and AM interact with complexes between CRLR and RAMP1, RAMP2 or RAMP3.

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Murugan, T., Rangaswamy Venkatesh, Kannappan Geetha, and Aly Abdou. "Synthesis, Spectral Investigation, DFT, Antibacterial, Antifungal and Molecular Docking Studies of Ni(II), Zn(II), Cd(II) Complexes of Tetradentate Schiff-Base Ligand." Asian Journal of Chemistry 35, no. 6 (2023): 1509–17. http://dx.doi.org/10.14233/ajchem.2023.27808.

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By refluxing 4-nitro-o-phenylenediamine and 5-nitro salicylaldehyde, a new Schiff base ligand was synthesized. By reacting the appropriate precursor with the tetradentate Schiff base ligand, three nitro-substituted nickel(II), zinc(II) and cadmium(II) complexes were synthesized. UV-Visible, FTIR and 1H NMR spectral investigations were used to characterize the ligand. Molar conductance, LC-MS, UV-visible and FTIR spectrum analysis were used to characterize the synthesized metal(II) complexes. The ligand and metal(II) complexes were also tested for antibacterial activity. DFT simulations were performed at the B3LYP/6-311G (d,p) and LanL2dz levels of theory were utilized to study the geometry of the Schiff base ligand and the metal(II) complexes. In addition, the molecular orbital occupancy of HOMO and LUMO, as well as the molecular electrostatic potential (MEP), were computed. Molecular docking investigation were conducted utilizing the active sites of the E. coli FabH-CoA complex (PDB ID: 1HNJ) receptor in order to detect the interactions between metal(II) complexes and define their likely binding locations.

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Belorusova, Anna Y., Maxime Bourguet, Steve Hessmann, Sandra Chalhoub, Bruno Kieffer, Sarah Cianférani, and Natacha Rochel. "Molecular determinants of MED1 interaction with the DNA bound VDR–RXR heterodimer." Nucleic Acids Research 48, no. 19 (September 29, 2020): 11199–213. http://dx.doi.org/10.1093/nar/gkaa775.

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Abstract The MED1 subunit of the Mediator complex is an essential coactivator of nuclear receptor-mediated transcriptional activation. While structural requirements for ligand-dependent binding of classical coactivator motifs of MED1 to numerous nuclear receptor ligand-binding domains have been fully elucidated, the recognition of the full-length or truncated coactivator by full nuclear receptor complexes remain unknown. Here we present structural details of the interaction between a large part of MED1 comprising its structured N-terminal and the flexible receptor-interacting domains and the mutual heterodimer of the vitamin D receptor (VDR) and the retinoid X receptor (RXR) bound to their cognate DNA response element. Using a combination of structural and biophysical methods we show that the ligand-dependent interaction between VDR and the second coactivator motif of MED1 is crucial for complex formation and we identify additional, previously unseen, interaction details. In particular, we identified RXR regions involved in the interaction with the structured N-terminal domain of MED1, as well as VDR regions outside the classical coactivator binding cleft affected by coactivator recruitment. These findings highlight important roles of each receptor within the heterodimer in selective recognition of MED1 and contribute to our understanding of the nuclear receptor-coregulator complexes.

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Mikhailenko, I., W. Considine, K. M. Argraves, D. Loukinov, B. T. Hyman, and D. K. Strickland. "Functional domains of the very low density lipoprotein receptor: molecular analysis of ligand binding and acid-dependent ligand dissociation mechanisms." Journal of Cell Science 112, no. 19 (October 1, 1999): 3269–81. http://dx.doi.org/10.1242/jcs.112.19.3269.

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The very low density lipoprotein (VLDL) receptor is closely related in structure to the low density lipoprotein receptor. The ectodomain of these endocytic receptors is composed of modules which include clusters of cysteine-rich class A repeats, epidermal growth factor (EGF)-like repeats, tyrosine-tryptophan-threonine-aspartic acid (YWTD) repeats and an O-linked sugar domain. To identify important functional regions within the ectodomain of the VLDL receptor, we produced a mutant receptor in which the EGF, YWTD and O-linked sugar domains were deleted. Cells transfected with the mutant receptor were able to bind and internalize (125)I-labeled receptor associated protein (RAP). In contrast to the wild-type receptor, however, RAP did not dissociate from the mutant receptor and consequently was not degraded. Immunofluoresence data indicated that once bound to the mutant receptor, fluorescent-labeled RAP co-localized with markers of the endosomal pathway, whereas, in cells expressing the wild-type receptor, RAP fluorescence co-localized with lysosomal markers. Thus this deleted region is responsible for ligand uncoupling within the endosomes. To identify regions responsible for ligand recognition, soluble receptor fragments containing the eight cysteine-rich class A repeats were produced. (125)I-RAP and (125)I-labeled urokinase-type plasminogen activator:plasminogen activator inhibitor type I (uPA:PAI-1) complexes bound to the soluble fragment with K(D, app) values of 0.3 and 14 nM, respectively. Deletion analysis demonstrate that high affinity RAP binding requires the first four cysteine-rich class A repeats (L1-4) in the VLDL receptor while the second repeat (L2) appears responsible for binding uPA:PAI-1 complexes. Together, these results confirm that ligand uncoupling occurs via an allosteric-type mechanism in which pH induced changes in the EGF and/or YWTD repeats alter the ligand binding properties at the amino-terminal portion of the molecule.

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Lovdal, T., E. Andersen, A. Brech, and T. Berg. "Fc receptor mediated endocytosis of small soluble immunoglobulin G immune complexes in Kupffer and endothelial cells from rat liver." Journal of Cell Science 113, no. 18 (September 15, 2000): 3255–66. http://dx.doi.org/10.1242/jcs.113.18.3255.

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Soluble circulating immunoglobulin G immune complexes are mainly eliminated by the liver, predominantly by uptake in the Kupffer cells, but also the liver endothelial cells seem to be of importance. In the present study we have followed the intracellular turnover of immune complexes after Fc(gamma) receptor mediated endocytosis in cultured rat liver endothelial cells and Kupffer cells by means of isopycnic centrifugation, DAB cross-linking and morphological techniques. For the biochemical experiments the antigen, dinitrophenylated bovine serum albumin (BSA), was labeled with radioiodinated tyramine cellobiose that cannot cross biological membranes and therefore traps labeled degradation products at the site of formation. The endocytic pathway followed by immune complexes was compared with that followed by scavenger receptor ligands, such as formaldehyde treated BSA and dinitrophenylated BSA, and the mannose receptor ligand ovalbumin. Both Kupffer cells and liver endothelial cells took up and degraded the immune complexes, but there was a clear delay in the degradation of immune complexes as compared to degradation of ligands taken up via scavenger receptors. The kinetics of the endocytosis of scavenger receptor ligand was unaffected by simultaneous uptake of immune complexes. Experiments using both biochemical and morphological techniques indicated that the delayed degradation was due to a late arrival of the immune complexes at the lysosomes, which partly was explained by retroendocytosis of immune complexes. Electron microscopy studies revealed that the immune complexes were retained in the early endosomes that remained accessible to other endocytic markers such as ovalbumin. In addition, the immune complexes were seen in multivesicular compartments apparently devoid of other endocytic markers. Finally, the immune complexes were degraded in the same lysosomes as the ligands of scavenger receptors. Thus, immune complexes seem to follow an endocytic pathway that is kinetically or maybe morphologically different from that followed by scavenger and mannose receptor ligands.

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Pandey, Kailash N. "Dynamics of internalization and sequestration of guanylyl cyclase/atrial natriuretic peptide receptor-A." Canadian Journal of Physiology and Pharmacology 79, no. 8 (August 1, 2001): 631–39. http://dx.doi.org/10.1139/y01-035.

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The guanylyl cyclase/natriuretic peptide receptor-A (NPRA), also referred to as GC-A, is a single polypeptide molecule. In its mature form, NPRA resides in the plasma membrane and consists of an extracellular ligand-binding domain, a single transmembrane-spanning region, and intracellular cytoplasmic domain that contains a protein kinase-like homology domain (KHD) and a guanylyl cyclase (GC) catalytic active site. The binding of atrial natriuretic peptide (ANP) to NPRA occurs at the plasma membrane; the receptor is synthesized on the polyribosomes of the endoplasmic reticulum, and is presumably degraded within the lysosomes. It is apparent that NPRA is a dynamic cellular macromolecule that traverses through different compartments of the cell through its lifetime. This review describes the experiments addressing the interaction of ANP with the NPRA, the receptor-mediated internalization and stoichiometric distribution of ANP-NPRA complexes from cell surface to cell interior, and its release into culture media. It is hypothesized that after internalization, the ligand-receptor complexes dissociate inside the cell and a population of NPRA recycles back to plasma membrane. Subsequently, some of the dissociated ligand molecules escape the lysosomal degradative pathway and are released intact into culture media, which reenter the cell by retroendocytotic mechanisms. By utilizing the pharmacologic and physiologic perturbants, the emphasis has been placed on the cellular regulation and processing of ligand-receptor complexes in intact cells. I conclude the discussion by examining the data available on the utilization of deletion mutations of NPRA cDNA, which has afforded experimental insights into the mechanisms the cell utilizes in modulating the expression and functioning of NPRA.Key words: atrial natriuretic peptide receptor-A, guanylyl cyclase receptors, ANP-binding, internalization and recycling of receptor, lysosomal hydrolysis.

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Ragoza, Matthew, Tomohide Masuda, and David Ryan Koes. "Generating 3D molecules conditional on receptor binding sites with deep generative models." Chemical Science 13, no. 9 (2022): 2701–13. http://dx.doi.org/10.1039/d1sc05976a.

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We generate 3D molecules conditioned on receptor binding sites by training a deep generative model on protein–ligand complexes. Our model uses the conditional receptor information to make chemically relevant changes to the generated molecules.

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Kongson, Jutarat, and Somkid Amornsamankul. "A Model of the Signal Transduction Process under a Delay." East Asian Journal on Applied Mathematics 7, no. 4 (November 2017): 741–51. http://dx.doi.org/10.4208/eajam.181016.300517a.

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AbstractThe signal transduction pathway is the important process of communication of the cells. It is the dynamical interaction between the ligand-receptor complexes and an inhibitor protein in second messenger synthesis. The signaling molecules are detected and bounded by receptors, typically G-Protein receptors, across the cell membrane and that in turns alerts intracellular molecules to stimulate a response or a desired consequence in the target cells. In this research, we consider a model of the signal transduction process consisting of a system of three differential equations which involve the dynamic interaction between an inhibitor protein and the ligand-receptor complexes in the second messenger synthesis. We will incorporate a delay τ in the time needed before the signal amplification process can take effect on the production of the ligand-receptor complex. We investigate persistence and stability of the system. It is shown that the system allows positive solutions and the positive equilibrium is locally asymptotically stable under suitable conditions on the system parameters.

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Ward, D. M., and J. Kaplan. "The rate of internalization of different receptor–ligand complexes in alveolar macrophages is receptor-specific." Biochemical Journal 270, no. 2 (September 1, 1990): 369–74. http://dx.doi.org/10.1042/bj2700369.

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To probe the mechanisms of endocytosis in alveolar macrophages, we examined the internalization rates of three different receptors. Initial rates of internalization for mannosylated BSA, diferric transferrin and alpha-macroglobulin-proteinase complexes were all different. Although the absolute rates of internalization varied depending on the cell preparation, transferrin was internalized at 10-20% and alpha-macroglobulin-proteinase complex at 40-60% of the rate of manosylated-BSA. Incubation of cells with transferrin did not affect the rate of internalization of mannosylated BSA or alpha-macroglobulin-proteinase complexes, and the rates of internalization were independent of receptor occupancy. These different internalization rates could not be ascribed to different rates of diacytosis. Altering the distribution of unoccupied surface receptors by either trypsin treatment of cells at 0 degree C or exposure to hyperosmotic solutions resulted in the absolute internalization rates being affected by the experimental condition, but the hierarchy in receptor internalization rates was maintained. The fact that a variety of conditions affect receptor internalization rates to the same degree implies the existence of co-ordinate regulation at a single rate-limiting step. Based on these results, we suggest that differences in internalization rate reflect the ability of ligand-receptor complexes to be captured by coated pits.

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Morelli, Maria Beatrice, Consuelo Amantini, Giorgio Santoni, Maura Pellei, Carlo Santini, Cristina Cimarelli, Enrico Marcantoni, et al. "Novel antitumor copper(ii) complexes designed to act through synergistic mechanisms of action, due to the presence of an NMDA receptor ligand and copper in the same chemical entity." New Journal of Chemistry 42, no. 14 (2018): 11878–87. http://dx.doi.org/10.1039/c8nj01763h.

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JUNTUNEN, Kari, Natacha ROCHEL, Dino MORAS, and Pirkko VIHKO. "Large-scale expression and purification of the human vitamin D receptor and its ligand-binding domain for structural studies." Biochemical Journal 344, no. 2 (November 24, 1999): 297–303. http://dx.doi.org/10.1042/bj3440297.

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We have expressed recombinant human vitamin D receptor and its ligand-binding domain in Spodoptera frugiperda (Sf9) insect cells with a 30-litre bioreactor. Both proteins were purified to apparent homogeneity with yields of 0.5-3.5 mg/l. Gel-filtration analyses indicated that the purified human vitamin D receptor and its ligand-binding domain were present as monomers in solution. The purified vitamin D receptor and its ligand-binding domain were demonstrated to bind 1α,25-dihydroxyvitamin D3 with high affinity, the Kd values ranging from 0.9 to 1.2 nM. Neutron scattering studies of the ligand-binding domain demonstrated that the samples are homogeneous and contain monomeric species of polypeptides. The purified vitamin D receptor binds to the vitamin D response elements of osteopontin and osteocalcin genes as a homodimer or as a heterodimer with the retinoid X receptor-αδAB and we were able to purify these complexes in quantities sufficient for crystallization studies. The results indicate that we can produce biologically active human vitamin D receptor and its ligand-binding domain in insect cells and purify them for functional and structural studies.

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Numata, Jorge, Alok Juneja, Dennis J. Diestler, and Ernst-Walter Knapp. "Influence of Spacer–Receptor Interactions on the Stability of Bivalent Ligand–Receptor Complexes." Journal of Physical Chemistry B 116, no. 8 (February 15, 2012): 2595–604. http://dx.doi.org/10.1021/jp211383s.

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Schneider, Helmut, Warak Chaovapong, David J. Matthews, Cyrus Karkaria, Robert T. Cass, Hangjun Zhan, Mark Boyle, Tony Lorenzini, Steve G. Elliott, and Lutz B. Giebel. "Homodimerization of Erythropoietin Receptor by a Bivalent Monoclonal Antibody Triggers Cell Proliferation and Differentiation of Erythroid Precursors." Blood 89, no. 2 (January 15, 1997): 473–82. http://dx.doi.org/10.1182/blood.v89.2.473.

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Abstract Erythropoietin (EPO) stimulates proliferation and differentiation of erythroid progenitor cells. Several lines of evidence indicate that the most likely mechanism of EPO receptor (EPO-R) activation by EPO is homodimerization of the receptor on the surface of erythrocyte precursors. Therefore, we argued that it should be possible to raise EPO-R monoclonal antibodies (MoAbs) that would activate the receptor by dimerization and thus mimic EPO action. We have identified such an agonist MoAb (MoAb34) directed against the extracellular EPO binding domain of the EPO-R. This bivalent IgG antibody triggers the proliferation of EPO-dependent cell lines and induces differentiation of erythroid precursors in vitro. In contrast, the monovalent Fab fragment, which cannot dimerize the receptor, is completely inactive. The mechanism of receptor activation by homodimerization implies that at high ligand concentrations the formation of 1:1 receptor/ligand complexes is favored over 2:1 complexes, thereby turning the ligand agonist into an antagonist. Thus, EPO and MoAb34 should self-antagonize at high concentrations in both cell proliferation and differentiation assays. Our data indeed demonstrate that EPO and MoAb34 antagonize ligand-dependent cell proliferation with IC50 values of approximately 20 and 2 μmol/L, respectively. Erythroid colony formation (BFUe) is inhibited at MoAb34 concentrations above 1 μmol/L. Furthermore, we analyzed the MoAb34:EPO-R interaction using a mathematic model describing antibody-mediated receptor dimerization. The data for proliferation and differentiation activity were consistent with the receptor dimer formation on the cell surface predicted by the model.

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Mecham, R. P., L. Whitehouse, M. Hay, A. Hinek, and M. P. Sheetz. "Ligand affinity of the 67-kD elastin/laminin binding protein is modulated by the protein's lectin domain: visualization of elastin/laminin-receptor complexes with gold-tagged ligands." Journal of Cell Biology 113, no. 1 (April 1, 1991): 187–94. http://dx.doi.org/10.1083/jcb.113.1.187.

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Video-enhanced microscopy was used to examine the interaction of elastin- or laminin-coated gold particles with elastin binding proteins on the surface of live cells. By visualizing the binding events in real time, it was possible to determine the specificity and avidity of ligand binding as well as to analyze the motion of the receptor-ligand complex in the plane of the plasma membrane. Although it was difficult to interpret the rates of binding and release rigorously because of the possibility for multiple interactions between particles and the cell surface, relative changes in binding have revealed important aspects of the regulation of affinity of ligand-receptor interaction in situ. Both elastin and laminin were found to compete for binding to the cell surface and lactose dramatically decreased the affinity of the receptor(s) for both elastin and laminin. These findings were supported by in vitro studies of the detergent-solubilized receptor. Further, immobilization of the ligand-receptor complexes through binding to the cytoskeleton dramatically decreased the ability of bound particles to leave the receptor. The changes in the kinetics of ligand-coated gold binding to living cells suggest that both laminin and elastin binding is inhibited by lactose and that attachment of receptor to the cytoskeleton increases its affinity for the ligand.

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Dominguez, Marta, Susana Alvarez, and Angel R. de Lera. "Natural and Structure-based RXR Ligand Scaffolds and Their Functions." Current Topics in Medicinal Chemistry 17, no. 6 (January 10, 2017): 631–62. http://dx.doi.org/10.2174/1568026616666160617072521.

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Retinoid X receptors (RXRs) are promiscuous partners of heterodimeric associations with other members of the Nuclear Receptor (NR) superfamily. Through these liaisons RXR ligands (“rexinoids”) either transcriptionally activate on their own the “permissive” subclass of heterodimers (PPAR/RXR, LXR/RXR, FXR/RXR) or synergize with partner ligands in the “non-permissive” subclass of heterodimers (RAR/RXR, VDR/RXR and TR/RXR). The nature and extent of the interaction of the ligand-receptor complexes with co-regulators, which is cell and context-dependent, results ultimately in transcriptional modulation of cognate gene networks. RXR modulators hold therapeutical potential for the treatment of cancer and other diseases related to nutrient acquisition and disposal, among them metabolic diseases. A rexinoid (bexarotene) has indeed reached the clinic for the treatment of cutaneous T-cell lymphoma. The modulation of RXR function by rexinoids acting as agonists, parcial agonists, inverse agonists or antagonists is encoded in the structure of the ligandreceptor complexes. A very large number of rexinoids with a wide structural diversity has been published. In addition to natural products and other ligands discovered by HTS or mere serendipity, most rexinoids have been rationally designed based on the structures of existing complexes with RXR determined by X-Ray or based on Molecular Modeling. Although the structural rationale for the modulation of the ligand-receptor complexes is reasonably well understood, it has not yet been possible to predict the correlation between ligand structure and physiological response, particularly in the case of heterodimer-selective rexinoids.

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Ibrahimi, Omar A., Brian K. Yeh, Anna V. Eliseenkova, Fuming Zhang, Shaun K. Olsen, Makoto Igarashi, Stuart A. Aaronson, Robert J. Linhardt, and Moosa Mohammadi. "Analysis of Mutations in Fibroblast Growth Factor (FGF) and a Pathogenic Mutation in FGF Receptor (FGFR) Provides Direct Evidence for the Symmetric Two-End Model for FGFR Dimerization." Molecular and Cellular Biology 25, no. 2 (January 15, 2005): 671–84. http://dx.doi.org/10.1128/mcb.25.2.671-684.2005.

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ABSTRACT Two competing models for fibroblast growth factor (FGF) receptor (FGFR) dimerization have recently emerged based on ternary FGF-FGFR-heparin crystal structures. In the symmetric two-end model, heparin promotes dimerization of two FGF-FGFR complexes by stabilizing bivalent interactions of the ligand and receptor through primary and secondary sites and by stabilizing direct receptor-receptor contacts. In the asymmetric model, there are no protein-protein contacts between the two FGF-FGFR complexes, which are bridged solely by heparin. To identify the correct mode of FGFR dimerization, we abolished interactions at the secondary ligand-receptor interaction site, which are observed only in the symmetric two-end model, using site-directed mutagenesis. Cellular studies and real-time binding assays, as well as matrix-assisted laser desorption ionization-time of flight analysis, demonstrate that loss of secondary ligand-receptor interactions results in diminished FGFR activation due to decreased dimerization without affecting FGF-FGFR binding. Additionally, structural and biochemical analysis of an activating FGFR2 mutation resulting in Pfeiffer syndrome confirms the physiological significance of receptor-receptor contacts in the symmetric two-end model and provides a novel mechanism for FGFR gain of function in human skeletal disorders. Taken together, the data validate the symmetric two-end model of FGFR dimerization and argue against the asymmetric model of FGFR dimerization.

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Amin, Divya N., and Gerald L. Hazelbauer. "The Chemoreceptor Dimer Is the Unit of Conformational Coupling and Transmembrane Signaling." Journal of Bacteriology 192, no. 5 (January 8, 2010): 1193–200. http://dx.doi.org/10.1128/jb.01391-09.

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ABSTRACT Transmembrane chemoreceptors are central components in bacterial chemotaxis. Receptors couple ligand binding and adaptational modification to receptor conformation in processes that create transmembrane signaling. Homodimers, the fundamental receptor structural units, associate in trimers and localize in patches of thousands. To what degree do conformational coupling and transmembrane signaling require higher-order interactions among dimers? To what degree are they altered by such interactions? To what degree are they inherent features of homodimers? We addressed these questions using nanodiscs to create membrane environments in which receptor dimers had few or no potential interaction partners. Receptors with many, few, or no interaction partners were tested for conformational changes and transmembrane signaling in response to ligand occupancy and adaptational modification. Conformation was assayed by measuring initial rates of receptor methylation, a parameter independent of receptor-receptor interactions. Coupling of ligand occupancy and adaptational modification to receptor conformation and thus to transmembrane signaling occurred with essentially the same sensitivity and magnitude in isolated dimers as for dimers with many neighbors. Thus, we conclude that the chemoreceptor dimer is the fundamental unit of conformational coupling and transmembrane signaling. This implies that in signaling complexes, coupling and transmembrane signaling occur through individual dimers and that changes between dimers in a receptor trimer or among trimer-based signaling complexes are subsequent steps in signaling.

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lngenhoven, Nikolaus, and Annette G. Beck-Sickinger. "Molecular Characterization of the Ligand-Receptor Interaction of Neuropeptide Y." Current Medicinal Chemistry 6, no. 11 (November 1999): 1055–66. http://dx.doi.org/10.2174/092986730611220401164224.

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Neuropeptide Y (NPY) consists of 36 amino acids and is one of the most abundant peptides in the peripheral and central nervous system. Several subtype•s of NPY receptors have been described (Y1• Y6) using segments and analogues of NPY. The Y 1-, Y2- and the Y5-receptor, which have been cloned, belong to the G-protein coupled hormone receptor family and will be specially addressed, because they are the endogenous binding sites of neuropeptide Y in human. In contrast, Y4-receptors recognize endogenous PP, Y3"receptors are discussed controversially and the y6-receptor is truncated in human. In this review, we summarize the data of neuropeptide Y with respect to ligand binding, selectivity, receptor structures and ligand- receptor complexes by using ligand analogues, site directed mutagenesis and photoaffinity labeling.

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Ahmed, A. R. H., G. W. J. Olivier, G. Adams, M. E. Erskine, R. G. Kinsman, S. K. Branch, S. H. Moss, L. J. Notarianni, and C. W. Pouton. "Isolation and partial purification of a melanocyte-stimulating hormone receptor from B16 murine melanoma cells. A novel approach using a cleavable biotinylated photoactivated ligand and streptavidin-coated magnetic beads." Biochemical Journal 286, no. 2 (September 1, 1992): 377–82. http://dx.doi.org/10.1042/bj2860377.

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The alpha-melanocyte-stimulating hormone (alpha-MSH) receptor of B16 mouse melanoma cells was characterized by photoaffinity labelling using radiolabelled photoactive derivatives of alpha-MSH. A doublet band of 43-46 kDa representing a ligand-receptor complex was identified. A novel adaptation of the streptovadin/biotin-based affinity system was used to isolate the alpha-MSH receptor. A probe was synthesized which contained biotin connected to a photolabelled alpha-MSH analogue via a cleavable disulphide linker and which displayed high affinity for the alpha-MSH receptor. Streptavidin-coated magnetic beads were used as a solid support instead of an affinity column. Covalently linked probe-receptor complexes solubilized in Triton X-100 were equilibrated with the beads, and after magnetic separation and washing, specifically bound complexes were treated with dithiothreitol to cleave the disulphide bridge in the biotin-peptide spacer arm and so release the receptor-ligand complex. The identity of the isolated protein was established by SDS/PAGE analysis. Methods to achieve purification to homogeneity and to allow quantitative isolation of the receptor are discussed.

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Liebman, M. N. "An approach to modelling specificity determinants in receptor ligand complexes." Acta Crystallographica Section A Foundations of Crystallography 43, a1 (August 12, 1987): C45. http://dx.doi.org/10.1107/s0108767387084307.

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Kastrup, J. S., P. Naur, B. Vestergaard, L. K. Skov, J. Egebjerg, and M. Gajhede. "Structural studies of kainate receptor GluR5 ligand-binding core complexes." Acta Crystallographica Section A Foundations of Crystallography 61, a1 (August 23, 2005): c234. http://dx.doi.org/10.1107/s0108767305090021.

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Chakrabortty, Tuhin, and Manoj M. Varma. "Equilibrium probability distribution for number of bound receptor-ligand complexes." American Journal of Physics 89, no. 1 (January 2021): 41–50. http://dx.doi.org/10.1119/10.0001898.

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Journal articles on the topic 'Receptor-ligand complexes'

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