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Journal articles on the topic 'Ligand binding'
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1
Seo, Sangmin, Jonghwan Choi, Soon Kil Ahn, Kil Won Kim, Jaekwang Kim, Jaehyuck Choi, Jinho Kim, and Jaegyoon Ahn. "Prediction of GPCR-Ligand Binding Using Machine Learning Algorithms." Computational and Mathematical Methods in Medicine 2018 (2018): 1–5. http://dx.doi.org/10.1155/2018/6565241.
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We propose a novel method that predicts binding of G-protein coupled receptors (GPCRs) and ligands. The proposed method uses hub and cycle structures of ligands and amino acid motif sequences of GPCRs, rather than the 3D structure of a receptor or similarity of receptors or ligands. The experimental results show that these new features can be effective in predicting GPCR-ligand binding (average area under the curve [AUC] of 0.944), because they are thought to include hidden properties of good ligand-receptor binding. Using the proposed method, we were able to identify novel ligand-GPCR bindings, some of which are supported by several studies.
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Aziz, Fitri Kusvila, Cantika Nukitasari, Fauziyah Ardli Oktavianingrum, Lita Windy Aryati, and Broto Santoso. "Hasil In Silico Senyawa Z12501572, Z00321025, SCB5631028 dan SCB13970547 dibandingkan Turunan Zerumbon terhadap Human Liver Glycogen Phosphorylase (1l5Q) sebagai Antidiabetes." Jurnal Kimia VALENSI 2, no. 2 (November 30, 2016): 120–24. http://dx.doi.org/10.15408/jkv.v2i2.4170.
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Abstrak Human Liver Glycogen Phosphorylase (HLGP), suatu katalis glikogen yang mengontrol pelepasan glukosa-1-fosfat glikogen dari hati. Enzim ini mempunyai peran sentral dalam luaran glukosa hati sehingga menjadi target obat antidiabetik. Kajian docking dilakukan pada komputer dengan prosesor Intel Pentium, RAM 1 GB dan Windows 7. Ligan yang digunakan adalah senyawa obat (Z12501572, Z00321025, SCB5631028 dan SCB13970547), dataset pembanding aktif glycogen phosphorylase outer dimer site (PYGL-out) dan decoysdari www.dekois.com dan turunan zerumbon. Protein dipisahkan dari ligan nativ dan semua ligan beserta protein dikonversi menggunakan PyRx. Visualisasi interaksi ligan-protein dihasilkan dengan program Protein-Ligand Interaction Profiler (PLIP) dan PyMOL. Senyawa ZER11 memiliki binding energy terbaik, yaitu -7.11 kkal/mol (untuk metode LGA dan GA) dan -4.08 kkal/mol untuk metode SA. Nilai binding energy tersebut lebih rendah dari pada nilai untuk ligan native dan satu dari keempat senyawa obat, terlebih jika dibandingkan dengan bindingaffinity dari dataset dan decoys. Interaksi ligan-protein pada ketiga metode tersebut ditemukan sangat bervariasi. Hal berbeda terjadi untuk metode Vina, bindingenergy ZER11 (-9.9 kkal/mol) lebih baik dibandingkan dengan ligan native dan keempat senyawa obat. Senyawa ZER11 memiliki residu interaksi yang sama dengan ligan native pada TRP67 dan LYS191 untuk metode Vina. Kata kunci: PDBID-1L5Q, AutoDock, docking molekuler, vina, antidiabetes Abstract Human Liver Glycogen Phosphorylase (HLGP) can catalyze glycogen and control the release of glucose-1-phosphate of glycogen from the liver. This enzyme has a central role in output rule of liver glucose as it can be used as an antidiabetic drug targets. Docking studies were carried out on PC with Intel Pentium, 1 GB RAM, in environment of Windows 7. Ligands used are drug compounds (Z12501572, Z00321025, SCB5631028 and SCB13970547), the active dataset comparator wasglycogenphosphorylase outer dimer site (PYGL-out) and decoys from www.dekois.com andzerumbonederivates. Protein was separated from its native ligand and all ligands including the protein were converted to pdbqt using PyRx. The interaction of protein-ligand was visualized using software of PLIP and PyMOL. Compound of ZER11 had the best binding energy were -7.11 kcal/mol (LGA and GA) and -4.08 kcal/mol (SA). The binding energy value was lower than the ligand native and one of the four drug compounds, especially compared with the binding affinity of dataset and decoys. Vice versa, for Vina method, the value of ligand binding protein for ZER11 (-9.9 kcal/mol) was better than the ligand native and all of the fourth drugcompounds. Vina result showed that ZER11 had the same residual interaction as the ligand native, which are TRP67 and LYS191. Keyword: PDBID-1L5Q, AutoDock, molecular docking, vina, antidiabetic DOI: http://dx.doi.org/10.15408/jkv.v0i0.4170
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Williams, Mobolaji. "Derangement model of ligand-receptor binding." Computational and Mathematical Biophysics 10, no. 1 (January 1, 2022): 123–66. http://dx.doi.org/10.1515/cmb-2022-0137.
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Abstract We introduce a derangement model of ligand-receptor binding that allows us to quantitatively frame the question “How can ligands seek out and bind to their optimal receptor sites in a sea of other competing ligands and suboptimal receptor sites?” To answer the question, we first derive a formula to count the number of partial generalized derangements in a list, thus extending the derangement result of Gillis and Even. We then compute the general partition function for the ligand-receptor system and derive the equilibrium expressions for the average number of bound ligands and the average number of optimally bound ligands. A visual model of squares assembling onto a grid allows us to easily identify fully optimal bound states. Equilibrium simulations of the system reveal its extremes to be one of two types, qualitatively distinguished by whether optimal ligand-receptor binding is the dominant form of binding at all temperatures and quantitatively distinguished by the relative values of two critical temperatures. One of those system types (termed “search-limited,” as it was in previous work) does not exhibit kinetic traps and we thus infer that biomolecular systems where optimal ligand-receptor binding is functionally important are likely to be search-limited.
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McNeely, Patrick M., Andrea N. Naranjo, Kimberly Forsten-Williams, and Anne Skaja Robinson. "A2AR Binding Kinetics in the Ligand Depletion Regime." SLAS DISCOVERY: Advancing the Science of Drug Discovery 22, no. 2 (September 27, 2016): 166–75. http://dx.doi.org/10.1177/1087057116667256.
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Ligand binding plays a fundamental role in stimulating the downstream signaling of membrane receptors. Here, ligand-binding kinetics of the full-length human adenosine A2A receptor (A2AR) reconstituted in detergent micelles were measured using a fluorescently labeled ligand via fluorescence anisotropy. Importantly, to optimize the signal-to-noise ratio, these experiments were conducted in the ligand depletion regime. In the ligand depletion regime, the assumptions used to determine analytical solutions for one-site binding models for either one or two ligands in competition are no longer valid. We therefore implemented a numerical solution approach to analyze kinetic binding data as experimental conditions approach the ligand depletion regime. By comparing the results from the numerical and the analytical solutions, we highlight the ligand-receptor ratios at which the analytical solution begins to lose predictive accuracy. Using the numerical solution approach, we determined the kinetic rate constants of the fluorescent ligand, FITC-APEC, and those for three unlabeled ligands using competitive association experiments. The association and dissociation rate constants of the unlabeled ligands determined from the competitive association experiments were then independently validated using competitive dissociation data. Based on this study, a numerical solution is recommended to determine kinetic ligand-binding parameters for experiments conducted in the ligand-depletion regime.
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Micovic, Vuk, Milovan Ivanovic, and Ljiljana Dosen-Micovic. "Structural requirements for ligands of the δ-opioid receptor." Journal of the Serbian Chemical Society 74, no. 11 (2009): 1207–17. http://dx.doi.org/10.2298/jsc0911207m.
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The ?-opioid receptor is sensitive to ligand geometry. In order to assist the synthesis of new ?-selective opioid ligands, the structure elements of ?-selective opioid ligands necessary for their effective binding were investigated. The automated docking procedure with a flexible ligand was used to simulate the binding of 17 ?-selective ligands to the ?-receptor. It was found that voluminous N-alkyl groups reduce the binding potency of naltrindole derivatives by preventing the ligands from adopting the preferred conformation in the receptor. This was confirmed by enantiospecific binding of chiral compounds where only one enantiomer adopts the naltrindole-like preferred conformation in the binding pocket. Voluminous groups replacing the hydroxyl group in the 3-hydroxybenzyl fragment of naltrindole analogs reduce the binding potency due to unfavorable steric interactions with the receptor. The two diastereoisomers of the potent ?-opioid ligand SNC80 confirmed the preferred binding conformation and the major receptor-ligand interactions.
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Tozer, Eileen Collins, Paul E. Hughes, and Joseph C. Loftus. "Ligand binding and affinity modulation of integrins." Biochemistry and Cell Biology 74, no. 6 (December 1, 1996): 785–98. http://dx.doi.org/10.1139/o96-085.
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Integrins are cell adhesion receptors that mediate cell–cell and cell–extracellular matrix interactions. The extracellular domains of these receptors possess binding sites for a diverse range of protein ligands. Ligand binding is divalent cation dependent and involves well-defined motifs in the ligand. Integrins can dynamically regulate their affinity for ligands (inside-out signaling). This ability to rapidly modulate their affinity state is key to their involvement in such processes as cell migration and platelet aggregation. This review will focus on two aspects of integrin function: first, on the molecular basis of ligand–integrin interactions and, second, on the underlying mechanisms controlling the affinity state of integrins for their ligands.Key words: integrins, ligand binding, affinity modulation.
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Marsh, Lorraine. "Strong Ligand-Protein Interactions Derived from Diffuse Ligand Interactions with Loose Binding Sites." BioMed Research International 2015 (2015): 1–6. http://dx.doi.org/10.1155/2015/746980.
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Many systems in biology rely on binding of ligands to target proteins in a single high-affinity conformation with a favorableΔG. Alternatively, interactions of ligands with protein regions that allow diffuse binding, distributed over multiple sites and conformations, can exhibit favorableΔGbecause of their higher entropy. Diffuse binding may be biologically important for multidrug transporters and carrier proteins. A fine-grained computational method for numerical integration of total bindingΔGarising from diffuse regional interaction of a ligand in multiple conformations using a Markov Chain Monte Carlo (MCMC) approach is presented. This method yields a metric that quantifies the influence on overall ligand affinity of ligand binding to multiple, distinct sites within a protein binding region. This metric is essentially a measure of dispersion in equilibrium ligand binding and depends on both the number of potential sites of interaction and the distribution of their individual predicted affinities. Analysis of test cases indicates that, for some ligand/protein pairs involving transporters and carrier proteins, diffuse binding contributes greatly to total affinity, whereas in other cases the influence is modest. This approach may be useful for studying situations where “nonspecific” interactions contribute to biological function.
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Weatherman, Ross V., Robert J. Fletterick, and Thomas S. Scanlan. "Nuclear-Receptor Ligands and Ligand-Binding Domains." Annual Review of Biochemistry 68, no. 1 (June 1999): 559–81. http://dx.doi.org/10.1146/annurev.biochem.68.1.559.
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Christensen, U., and L. Mølgaard. "Positive co-operative binding at two weak lysine-binding sites governs the Glu-plasminogen conformational change." Biochemical Journal 285, no. 2 (July 15, 1992): 419–25. http://dx.doi.org/10.1042/bj2850419.
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The kinetics of a series of Glu-plasminogen ligand-binding processes were investigated at pH 7.8 and 25 degrees C (in 0.1 M-NaCl). The ligands include compounds analogous to C-terminal lysine residues and to normal lysine residues. Changes of the Glu-plasminogen protein fluorescence were measured in a stopped-flow instrument as a function of time after rapid mixing of Glu-plasminogen and ligand at various concentrations. Large positive fluorescence changes (approximately 10%) accompany the ligand-induced conformational changes of Glu-plasminogen resulting from binding at weak lysine-binding sites. Detailed studies of the concentration-dependencies of the equilibrium signals and the rate constants of the process induced by various ligands showed the conformational change to involve two sites in a concerted positive co-operative process with three steps: (i) binding of a ligand at a very weak lysine-binding site that preferentially, but not exclusively, binds C-terminal-type lysine ligands, (ii) the rate-determining actual-conformational-change step and (iii) binding of one more lysine ligand at a second weak lysine-binding site that then binds the ligand more tightly. Further, totally independent initial small negative fluorescence changes (approximately 2-4%) corresponding to binding at the strong lysine-binding site of kringle 1 [Sottrup-Jensen, Claeys, Zajdel, Petersen & Magnusson (1978) Prog. Chem. Fibrinolysis Thrombolysis 3, 191-209] were observed for the C-terminal-type ligands. The finding that the conformational change in Glu-plasminogen involves two weak lysine-binding sites indicates that the effect cannot be assigned to any single kringle and that the problem of whether kringle 4 or kringle 5 is responsible for the process resolves itself. Probably kringle 4 and 5 are both participating. The involvement of two lysine binding-sites further makes the high specificity of Glu-plasminogen effectors more conceivable.
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Cao, Chen, Lincong Wang, Xiaoyang Chen, Shuxue Zou, Guishen Wang, and Shutan Xu. "Amino Acids in Nine Ligand-Prefer Ramachandran Regions." BioMed Research International 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/757495.
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Several secondary structures, such asπ-helix and left-handed helix, have been frequently identified at protein ligand-binding sites. A secondary structure is considered to be constrained to a specific region of dihedral angles. However, a comprehensive analysis of the correlation between main chain dihedral angles and ligand-binding sites has not been performed. We undertook an extensive analysis of the relationship between dihedral angles in proteins and their distance to ligand-binding sites, frequency of occurrence, molecular potential energy, amino acid composition, van der Waals contacts, and hydrogen bonds with ligands. The results showed that the values of dihedral angles have a strong preference for ligand-binding sites at certain regions in the Ramachandran plot. We discovered that amino acids preceding the ligand-preferϕ/ψbox residues are exposed more to solvents, whereas amino acids following ligand-preferϕ/ψbox residues form more hydrogen bonds and van der Waals contacts with ligands. Our method exhibited a similar performance compared with the program Ligsite-csc for both ligand-bound structures and ligand-free structures when just one ligand-binding site was predicted. These results should be useful for the prediction of protein ligand-binding sites and for analysing the relationship between structure and function.
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Chen, Xun, Steven Stout, Uwe Mueller, George Boykow, Richard Visconti, Phieng Siliphaivanh, Kerrie Spencer, et al. "Label-Free, LC-MS-Based Assays to Quantitate Small-Molecule Antagonist Binding to the Mammalian BLT1 Receptor." SLAS DISCOVERY: Advancing the Science of Drug Discovery 22, no. 9 (August 1, 2017): 1131–41. http://dx.doi.org/10.1177/2472555217719748.
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We have developed and validated label-free, liquid chromatography–mass spectrometry (LC-MS)-based equilibrium direct and competition binding assays to quantitate small-molecule antagonist binding to recombinant human and mouse BLT1 receptors expressed in HEK 293 cell membranes. Procedurally, these binding assays involve (1) equilibration of the BLT1 receptor and probe ligand, with or without a competitor; (2) vacuum filtration through cationic glass fiber filters to separate receptor-bound from free probe ligand; and (3) LC-MS analysis in selected reaction monitoring mode for bound probe ligand quantitation. Two novel, optimized probe ligands, compounds 1 and 2, were identified by screening 20 unlabeled BLT1 antagonists for direct binding. Saturation direct binding studies confirmed the high affinity, and dissociation studies established the rapid binding kinetics of probe ligands 1 and 2. Competition binding assays were established using both probe ligands, and the affinities of structurally diverse BLT1 antagonists were measured. Both binding assay formats can be executed with high specificity and sensitivity and moderate throughput (96-well plate format) using these approaches. This highly versatile, label-free method for studying ligand binding to membrane-associated receptors should find broad application as an alternative to traditional methods using labeled ligands.
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Jia, Zhe, Lin Li, Yunhui Peng, Feng Ding, and Emil Alexov. "The capricious electrostatic force: Revealing the signaling pathway in integrin α2-I domain." Journal of Theoretical and Computational Chemistry 17, no. 03 (May 2018): 1840001. http://dx.doi.org/10.1142/s0219633618400011.
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Integrins are cellular adhesion proteins located on cell surface. They are known to have open and closed conformations that correspond to high and low binding affinity to ligands, respectively. Integrin [Formula: see text]2 binds to the ligands via the ligand binding domain, [Formula: see text]2-I domain, which also has open and closed conformations. Experimentally, the closed to open conformation change is shown to be triggered by pulling the C-terminal away from the ligand binding site, but how the signal propagates from the distant C-terminal to the binding site is unknown. To explain the mechanisms of the conformation change, we built models of the [Formula: see text]2-I domain open and closed conformations in ligand free and ligand bound states, respectively. We found that the signaling pathway consists of F313-I280-V252 residues that connect the C-terminal and the ligand binding site. The pathway is highly conserved as revealed by a protein sequence analysis among 55 species. Furthermore, MM/PBSA energy calculations on the stabilities and ligand binding affinities of the closed and open conformations are consistent with experimental measurements. The open conformation is more favorable for ligand binding, and the closed conformation is more stable in unbound state. Energy analysis also revealed the “hot spots” for ligand binding, and most residues that contribute strongly to ligand binding free energy are highly conserved in evolution. In addition, the electrostatic analysis showed that the closed conformation has stronger long-range electrostatic attraction to the ligand compared with the open conformation. The difference is caused by the rearrangement of several charged residues during the binding. These observations make us suggest that the integrin [Formula: see text]2-I domain binding process involves the two-step “dock-lock” mechanism. The closed conformation first attracts the ligand from a long distance and afterwards, the open conformation locks the ligand at the binding site with high binding affinity.
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Souza, P. C. T., A. C. Puhl, L. Martínez, R. Aparício, A. S. Nascimento, A. C. M. Figueira, P. Nguyen, P. Webb, M. S. Skaf, and I. Polikarpov. "Identification of a New Hormone-Binding Site on the Surface of Thyroid Hormone Receptor." Molecular Endocrinology 28, no. 4 (April 1, 2014): 534–45. http://dx.doi.org/10.1210/me.2013-1359.
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Abstract Thyroid hormone receptors (TRs) are members of the nuclear receptor superfamily of ligand-activated transcription factors involved in cell differentiation, growth, and homeostasis. Although X-ray structures of many nuclear receptor ligand-binding domains (LBDs) reveal that the ligand binds within the hydrophobic core of the ligand-binding pocket, a few studies suggest the possibility of ligands binding to other sites. Here, we report a new x-ray crystallographic structure of TR-LBD that shows a second binding site for T3 and T4 located between H9, H10, and H11 of the TRα LBD surface. Statistical multiple sequence analysis, site-directed mutagenesis, and cell transactivation assays indicate that residues of the second binding site could be important for the TR function. We also conducted molecular dynamics simulations to investigate ligand mobility and ligand-protein interaction for T3 and T4 bound to this new TR surface-binding site. Extensive molecular dynamics simulations designed to compute ligand-protein dissociation constant indicate that the binding affinities to this surface site are of the order of the plasma and intracellular concentrations of the thyroid hormones, suggesting that ligands may bind to this new binding site under physiological conditions. Therefore, the second binding site could be useful as a new target site for drug design and could modulate selectively TR functions.
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Mailfait, S., E. Thoreau, D. Belaiche, and P. Formstecher And B Sablonnie. "Critical role of the H6-H7 loop in the conformational adaptation of all-trans retinoic acid and synthetic retinoids within the ligand-binding site of RARalpha." Journal of Molecular Endocrinology 24, no. 3 (June 1, 2000): 353–64. http://dx.doi.org/10.1677/jme.0.0240353.
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The pleiotropic effects of the natural and synthetic retinoids are mediated by the activation of the two subfamilies of nuclear receptors, the retinoic acid receptors (RARs) and the retinoic X receptors (RXRs). At the molecular level, these events begin with the specific ligand recognition by a nuclear receptor subtype. The adaptation of ligands to the receptor binding site leads to an optimal number of interactions for binding and selectivity which justifies elucidation of the structural requirements of the ligand binding pocket. To explore the contribution of H6-H7 loop folding in the ligand-induced conformational changes explained by the mouse-trap model, four RARalpha mutants were constructed. Ligand binding and transactivation studies revealed that three residues from the H6-H7 loop (Gly(301), Phe(302) and Gly(303)) are critical for the conformational adaptation of both synthetic agonists and antagonists. Model building and analysis of both RARalpha-ATRA and RARalpha-CD367 complexes demonstrate that accommodation of CD367 results in a less tight contact of the saturated ring of this ligand with the amino acid side chains of the receptor ligand-binding pocket compared with that of ATRA. According to the flexibility of the agonists tested (ATRA>TTNPB=Am580> CD367), we observed a decrease in binding that was dependent on ligand structure rigidity. In contrast, the binding and transactivating activities of the L266A mutant confirmed the structural constraints imposed by synthetic ligands on binding affinity for the receptor and revealed that subtle local rearrangements induced by specific conformational adaptation changes result in different binding affinities. Our results illustrate the dynamic nature of the interaction between RARalpha and its ligands and demonstrate the critical role of the H6-H7 loop in the binding of both synthetic retinoid agonists and antagonists.
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Hu, Guodong, Haiyan Li, Shicai Xu, and Jihua Wang. "Ligand Binding Mechanism and Its Relationship with Conformational Changes in Adenine Riboswitch." International Journal of Molecular Sciences 21, no. 6 (March 11, 2020): 1926. http://dx.doi.org/10.3390/ijms21061926.
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Riboswitches are naturally occurring RNA aptamers that control the expression of essential bacterial genes by binding to specific small molecules. The binding with both high affinity and specificity induces conformational changes. Thus, riboswitches were proposed as a possible molecular target for developing antibiotics and chemical tools. The adenine riboswitch can bind not only to purine analogues but also to pyrimidine analogues. Here, long molecular dynamics (MD) simulations and molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) computational methodologies were carried out to show the differences in the binding model and the conformational changes upon five ligands binding. The binding free energies of the guanine riboswitch aptamer with C74U mutation complexes were compared to the binding free energies of the adenine riboswitch (AR) aptamer complexes. The calculated results are in agreement with the experimental data. The differences for the same ligand binding to two different aptamers are related to the electrostatic contribution. Binding dynamical analysis suggests a flexible binding pocket for the pyrimidine ligand in comparison with the purine ligand. The 18 μs of MD simulations in total indicate that both ligand-unbound and ligand-bound aptamers transfer their conformation between open and closed states. The ligand binding obviously affects the conformational change. The conformational states of the aptamer are associated with the distance between the mass center of two key nucleotides (U51 and A52) and the mass center of the other two key nucleotides (C74 and C75). The results suggest that the dynamical character of the binding pocket would affect its biofunction. To design new ligands of the adenine riboswitch, it is recommended to consider the binding affinities of the ligand and the conformational change of the ligand binding pocket.
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Genest, Alexander, Sven Krüger, Alexei B. Gordienko, and Notker Rösch. "Gold-Thiolate Clusters: A Relativistic Density Functional Study of the Model Species Au13(SR)n, R = H, CH3, n = 4, 6, 8." Zeitschrift für Naturforschung B 59, no. 11-12 (December 1, 2004): 1585–99. http://dx.doi.org/10.1515/znb-2004-11-1232.
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The binding of sulfanyl and alkylsulfanyl model ligands to gold clusters was studied for the case of Au13(SR)n with R = H, CH3 and n = 4, 6, 8. Accurate all-electron electronic structure calculations and geometry optimizations of these gold-thiolate clusters have been performed with a scalar relativistic Kohn-Sham procedure as implemented in the density functional program PARAGAUSS. In all structures obtained, bridge coordination was preferred for both types of ligands; no higher coordinated sites where occupied. While in many cases ligand decoration did not change the overall structure of the Au13 core, also more open structures with Au-Au distances elongated beyond the bulk value have been obtained. The effects due to increasing ligand decoration were small: a small decrease of the binding energy per ligand does not exclude higher ligand coverages. The differences between the model ligands SH and SCH3 were consistent in all cases considered: SCH3 exhibits weaker binding and a slightly smaller charge separation between cluster core and ligand shell, which amounts up to about 1.5 e for 8 ligands. Overall, the Au13 core of the clusters was found to be quite flexible. This can be rationalized by the fact that the calculated binding energy per ligand is comparable or even exceeds the binding energy per atom in Au13.
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Obermoeller-McCormick, L. M., Y. Li, H. Osaka, D. J. FitzGerald, A. L. Schwartz, and G. Bu. "Dissection of receptor folding and ligand-binding property with functional minireceptors of LDL receptor-related protein." Journal of Cell Science 114, no. 5 (March 1, 2001): 899–908. http://dx.doi.org/10.1242/jcs.114.5.899.
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The LDL receptor-related protein (LRP) is a large, multifunctional endocytic receptor that binds and endocytoses a variety of structurally and functionally distinct ligands. LRP contains four putative ligand-binding domains. However, only domains II, III and IV, but not domain I, bind the receptor-associated protein (RAP), a molecular chaperone and universal antagonist for LRP. In order to dissect the function of RAP in LRP folding and to examine the ligand-binding properties of LRP, we generated LRP minireceptors that represent each of the four putative ligand-binding domains (termed mLRP1, mLRP2, mLRP3 and mLRP4, respectively). We found that proper folding and trafficking of mLRP2, mLRP3, mLRP4, but not mLRP1, is facilitated by coexpression of RAP. When these mLRPs were stably expressed in Chinese Hamster Ovary cells that lack the endogenous LRP, we found that each of these receptors was processed and traffics through the secretory pathway. Cell surface expression of these minireceptors was quantitatively examined by flow cytometric analyses. Using these minireceptor cell lines to map the ligand-binding domains, we found that although the majority of LRP ligands bind to both domain II and domain IV, Pseudomonas exotoxin A utilizes only domain IV for its binding to LRP. We conclude that while domains II and IV of LRP share many ligand-binding properties, each of the putative ligand-binding domains of LRP is unique in its contribution to ligand binding.
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Iatmanen-Harbi, Soria, lucile Senicourt, Vassilios Papadopoulos, Olivier Lequin, and Jean-Jacques Lacapere. "Characterization of the High-Affinity Drug Ligand Binding Site of Mouse Recombinant TSPO." International Journal of Molecular Sciences 20, no. 6 (March 21, 2019): 1444. http://dx.doi.org/10.3390/ijms20061444.
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The optimization of translocator protein (TSPO) ligands for Positron Emission Tomography as well as for the modulation of neurosteroids is a critical necessity for the development of TSPO-based diagnostics and therapeutics of neuropsychiatrics and neurodegenerative disorders. Structural hints on the interaction site and ligand binding mechanism are essential for the development of efficient TSPO ligands. Recently published atomic structures of recombinant mammalian and bacterial TSPO1, bound with either the high-affinity drug ligand PK 11195 or protoporphyrin IX, have revealed the membrane protein topology and the ligand binding pocket. The ligand is surrounded by amino acids from the five transmembrane helices as well as the cytosolic loops. However, the precise mechanism of ligand binding remains unknown. Previous biochemical studies had suggested that ligand selectivity and binding was governed by these loops. We performed site-directed mutagenesis to further test this hypothesis and measured the binding affinities. We show that aromatic residues (Y34 and F100) from the cytosolic loops contribute to PK 11195 access to its binding site. Limited proteolytic digestion, circular dichroism and solution two-dimensional (2-D) NMR using selective amino acid labelling provide information on the intramolecular flexibility and conformational changes in the TSPO structure upon PK 11195 binding. We also discuss the differences in the PK 11195 binding affinities and the primary structure between TSPO (TSPO1) and its paralogous gene product TSPO2.
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Klunk, W. E., J. W. Pettegrew, and D. J. Abraham. "Two simple methods for quantifying low-affinity dye-substrate binding." Journal of Histochemistry & Cytochemistry 37, no. 8 (August 1989): 1293–97. http://dx.doi.org/10.1177/37.8.2666512.
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Binding with low-affinity ligands, such as histological dyes, can be difficult to quantitate owing to the dissociation of bound ligand with washing or the retention of nonspecifically bound ligand because of incomplete washing. The present report describes two simple, rapid methods of discriminating bound from free ligand without the need for washing steps. One method is based on the spectral changes induced in a dye ligand, Congo red, on binding to the "receptor" insulin fibrils. This method discriminates spectrophotometrically between bound and free ligand without requiring any physical separation of the two forms. No radioactive ligands are necessary, and, by using disposable cuvettes, the entire binding assay can be done in a single container without the need for transfers. The second method employs a non-traditional filtration approach that avoids the need for a washing step by measuring the decrease in concentration of the dye ligand in the filtrate rather than by applying the usual approach of measuring the absolute amount of ligand bound to the precipitated "receptor." Both methods show saturation of binding sites and give similar values for the KD and Bmax.
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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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Urien, S., F. Brée, B. Testa, and J. P. Tillement. "pH-dependency of basic ligand binding to α1-acid glycoprotein (orosomucoid)." Biochemical Journal 280, no. 1 (November 15, 1991): 277–80. http://dx.doi.org/10.1042/bj2800277.
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The binding interactions of a series of basic ligands with alpha 1-acid glycoprotein (AAG) were examined as a function of pH. The binding to AAG increased with increasing pH, and the binding data were satisfactorily fitted to a model that incorporates the effect of pH and discriminates the association constants of neutral (non-protonated) and protonated forms of ligands. It was shown that ligands in the neutral form have a markedly higher affinity for AAG than the protonated forms, resulting in a concomitant decrease in the pKa of bound ligands. The u.v.-visible difference spectra generated upon binding of a representative ligand to AAG also showed that there was a contribution to the binding arising from the deprotonation of the ligand. It is suggested that all tested ligands bind similarly to AAG and that hydrophobic interactions dominate high-affinity binding to AAG.
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Monaco, Serena, Jonathan Ramírez-Cárdenas, Ana Teresa Carmona, Inmaculada Robina, and Jesus Angulo. "Inter-Ligand STD NMR: An Efficient 1D NMR Approach to Probe Relative Orientation of Ligands in a Multi-Subsite Protein Binding Pocket." Pharmaceuticals 15, no. 8 (August 21, 2022): 1030. http://dx.doi.org/10.3390/ph15081030.
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In recent years, Saturation Transfer Difference NMR (STD NMR) has been proven to be a powerful and versatile ligand-based NMR technique to elucidate crucial aspects in the investigation of protein-ligand complexes. Novel STD NMR approaches relying on “multi-frequency” irradiation have enabled us to even elucidate specific ligand-amino acid interactions and explore the binding of fragments in previously unknown binding subsites. Exploring multi-subsite protein binding pockets is especially important in Fragment Based Drug Discovery (FBDD) to design leads of increased specificity and efficacy. We hereby propose a novel multi-frequency STD NMR approach based on direct irradiation of one of the ligands in a multi-ligand binding process, to probe the vicinity and explore the relative orientation of fragments in adjacent binding sub-sites, which we called Inter-Ligand STD NMR (IL-STD NMR). We proved its applicability on (i) a standard protein-ligand system commonly used for ligand-observed NMR benchmarking: Naproxen as bound to Bovine Serum Albumin, and (ii) the biologically relevant system of Cholera Toxin Subunit B and two inhibitors adjacently bound within the GM1 binding site. Relative to Inter-Ligand NOE (ILOE), the current state-of-the-art methodology to probe relative orientations of adjacent ligands, IL-STD NMR requires about one tenth of the experimental time and protein consumption, making it a competitive methodology with the potential to be applied in the pharmaceutical industries.
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Honda, Shigenori, Hirokazu Kashiwagi, Teruo Kiyoi, Hisashi Kato, Satoru Kosugi, Masamichi Shiraga, Yoshiyuki Kurata, and Yoshiaki Tomiyama. "Amino acid mutagenesis within ligand-binding loops in αv confers loss-of-function or gain-of-function phenotype on integrin αvβ3." Thrombosis and Haemostasis 92, no. 11 (2004): 1092–98. http://dx.doi.org/10.1160/th04-04-0257.
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SummaryThe crystal structure of αvβ3 in complex with a cyclic RGDcontaining ligand has recently been demonstrated. However, the functional significance of each residue within ligand binding loops has not been fully elucidated. Here, by employing alaninescanning mutagenesis, we have examined the functional role of ligand contact residues in αv. Tyr178 –> Ala substitution (Tyr178Ala) and Asp218Ala abolished a monovalent ligand, WOW-1 Fab binding as well as soluble fibrinogen binding, which is in perfect agreement with the crystallography. However, Asp150Ala showed no or only a modest inhibition of ligand binding. In contrast, Tyr substitution at Ala215 (Ala215Tyr) increased WOW-1 Fab binding, suggesting that the substitution increased the integrin affinity. The adhesion assay to immobilized fibrinogen showed essentially the same data as obtained using soluble ligands. Our present data indicate that Tyr178 and Asp218, but not Asp150 in αv is critically involved in ligand-binding and that Ala215 could regulate the affinity of αvβ3.
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Mondoro, TH, CD Wall, MM White, and LK Jennings. "Selective induction of a glycoprotein IIIa ligand-induced binding site by fibrinogen and von Willebrand factor." Blood 88, no. 10 (November 15, 1996): 3824–30. http://dx.doi.org/10.1182/blood.v88.10.3824.bloodjournal88103824.
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Ligand-induced binding sites (LIBS) are neoantigenic regions of glycoprotein (GP)IIb-IIIa that are exposed upon interaction of the receptor with the ligand fibrinogen or the ligand recognition sequence (RGDS). LIBS have been suggested to contribute to postreceptor occupancy events such as full-scale platelet aggregation, adhesion to collagen, and clot retraction. This study examined the induction requirements of a GPIIIa LIBS with regard to ligand specificity. Through the use of the anti-LIBS D3, we report that this complex- activating antibody induces fibrinogen-and von Willebrand factor-binding to GPIIb-IIIa on intact platelets. Bound ligand was detected by flow cytometric analysis and platelet aggregation assays. These bound ligands increased the number of D3-binding sites and altered the affinity of D3 for GPIIb-IIIa on platelets. In contrast, activation of platelet GPIIb-IIIa by D3 did not increase the binding of another RGD- containing ligand, vitronectin. Furthermore, bound vitronectin on thrombin-stimulated platelets did not cause the expression of the D3 LIBS epitope. We conclude direct activation of GPIIb-IIIa in the absence of platelet activation results in selective ligand interaction and that D3 LIBS induction requires the binding of the multivalent ligands, fibrinogen or von Willebrand factor. Thus, the region of GPIIIa recognized by D3 may be an important regulatory domain in ligand- receptor interactions that directly mediate platelet aggregation.
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Newham, Peter, Sue E. Craig, Katherine Clark, A. Paul Mould, and Martin J. Humphries. "Analysis of Ligand-Induced and Ligand-Attenuated Epitopes on the Leukocyte Integrin α4β1: VCAM-1, Mucosal Addressin Cell Adhesion Molecule-1, and Fibronectin Induce Distinct Conformational Changes." Journal of Immunology 160, no. 9 (May 1, 1998): 4508–17. http://dx.doi.org/10.4049/jimmunol.160.9.4508.
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Abstract The leukocyte integrin α4β1 is a receptor for both cell surface ligands (VCAM-1 and mucosal addressin cell adhesion molecule-1 (MAdCAM-1)) and extracellular matrix components (fibronectin). Through regulated interactions with these molecules, α4β1 mediates leukocyte migration from the vasculature at sites of inflammation. Regulation of integrin activity plays a key role in controlling leukocyte-adhesive events and appears to be partly determined by changes in integrin conformation. Several mAbs that recognize ligand-induced binding site epitopes on integrins have been characterized, and a subset of these mAbs are capable of stimulating integrin-ligand binding. Conversely, some mAbs recognize epitopes that are attenuated by ligand engagement and allosterically inhibit ligand binding. To gain insight into ligand-specific effects on integrin conformation, we have examined the ability of different ligands to modulate the binding of four distinct classes (A, B1, B2, and C) of anti-α4 Abs to α4β1. VCAM-1 attenuated B (antifunctional) class epitopes via an allosteric mechanism and also allosterically inhibited the binding of the function-blocking anti-β1 mAb 13. Additional α4β1 ligands (fibronectin fragments, MAdCAM-1, and the CS1 peptide) also inhibited mAb 13-integrin binding; however, the epitopes of the class B anti-α4 mAbs were attenuated by the fibronectin fragments, but not by MAdCAM-1 or the CS1 peptide. Of the two anti-α4 class A mAbs examined, one recognized an epitope that was induced uniquely by VCAM-1. Taken together, these data suggest that overlapping but distinct binding mechanisms exist for different α4β1 ligands and that distinct conformational changes are induced upon integrin engagement by different ligands.
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Akke, Mikael. "Conformational dynamics and thermodynamics of protein–ligand binding studied by NMR relaxation." Biochemical Society Transactions 40, no. 2 (March 21, 2012): 419–23. http://dx.doi.org/10.1042/bst20110750.
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Protein conformational dynamics can be critical for ligand binding in two ways that relate to kinetics and thermodynamics respectively. First, conformational transitions between different substates can control access to the binding site (kinetics). Secondly, differences between free and ligand-bound states in their conformational fluctuations contribute to the entropy of ligand binding (thermodynamics). In the present paper, I focus on the second topic, summarizing our recent results on the role of conformational entropy in ligand binding to Gal3C (the carbohydrate-recognition domain of galectin-3). NMR relaxation experiments provide a unique probe of conformational entropy by characterizing bond-vector fluctuations at atomic resolution. By monitoring differences between the free and ligand-bound states in their backbone and side chain order parameters, we have estimated the contributions from conformational entropy to the free energy of binding. Overall, the conformational entropy of Gal3C increases upon ligand binding, thereby contributing favourably to the binding affinity. Comparisons with the results from isothermal titration calorimetry indicate that the conformational entropy is comparable in magnitude to the enthalpy of binding. Furthermore, there are significant differences in the dynamic response to binding of different ligands, despite the fact that the protein structure is virtually identical in the different protein–ligand complexes. Thus both affinity and specificity of ligand binding to Gal3C appear to depend in part on subtle differences in the conformational fluctuations that reflect the complex interplay between structure, dynamics and ligand interactions.
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Fukuzawa, Kaori, Kazuo Kitaura, K. Nakata, Tsuguchika Kaminuma, and T. Nakano. "Fragment molecular orbital study of the binding energy of ligands to the estrogen receptor." Pure and Applied Chemistry 75, no. 11-12 (January 1, 2003): 2405–10. http://dx.doi.org/10.1351/pac200375112405.
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We examined the published data for the binding affinity of typical ligands to the α-subtype of the human estrogen receptor with use of an approximate molecular orbital method applicable to interacting molecular clusters. An ab initio procedure for "molecular fragments" proposed recently to deal with such macromolecules as proteins was applied to the molecular orbital calculations. The receptor protein was primarily modeled using 50 amino acid residues surrounding the ligand. For a few ligand-receptor complexes, the binding energy was also calculated with use of 241 amino acid residues contained in the entire binding domain. No significant difference was found in the calculated binding energy between the complex modeled with ligand-surrounding 50 amino acids and that with residues of the entire domain. The calculated binding energy was correlated very well with the published relative binding affinity for typical ligands.
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Rifai, Yusnita. "SEARCH FOR GLIOMA DIRECT BINDING SITE OF ALKALOID USING PROTEIN-LIGAND ANT SYSTEM®." Asian Journal of Pharmaceutical and Clinical Research 11, no. 15 (October 3, 2018): 65. http://dx.doi.org/10.22159/ajpcr.2018.v11s3.30034.
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Objective: This research aims to know the best affinity and the best chemical conformation of anticancer compounds from alkaloid groups that have closed direction to Glioma-associated oncogene using protein-ligand ant system (PLANTS®). The interaction energy and hydrogen bond are included as evaluated targets.Methods: In this research, 27 ligands with root mean square deviation score at 1.614 Å and cyclopamine as native ligand are used. Meanwhile, staurosporinone acts as gliomas directed-binding-site-internal-control. Each ligand is docked in GLI with Protein Data Bank code 2GLI using two methods, GLI contains water and without water.Results: PLANTS® score for native ligand in the first and the second method is −73.9002 and −73.2700, respectively. Pancracristine, homoharringtonine, and sanguinarine showed PLANTS® score closed to the cyclopamine score result, but their hydrogen bond interaction differed from native ligan interaction. Evodiamine ligand has a good score and hydrogen bond to the same amino acid of protein GLI, which are GLU 175 and THR 173. This result indicated that evodiamine has the same identical mechanism as staurosporinone.Conclusion: The evodiamine is determined to have the same working mechanism as a GLI inhibitor.
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Chitnis, C. E., A. Chaudhuri, R. Horuk, A. O. Pogo, and L. H. Miller. "The domain on the Duffy blood group antigen for binding Plasmodium vivax and P. knowlesi malarial parasites to erythrocytes." Journal of Experimental Medicine 184, no. 4 (October 1, 1996): 1531–36. http://dx.doi.org/10.1084/jem.184.4.1531.
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Plasmodium vivax and the related simian malarial parasite P. knowlesi use the Duffy blood group antigen as a receptor to invade human erythrocytes and region II of the parasite ligands for binding to this erythrocyte receptor. Here, we identify the peptide within the Duffy blood group antigen of human and rhesus erythrocytes to which the P. vivax and P. knowlesi ligands bind. Peptides from the NH2-terminal extracellular region of the Duffy antigen were tested for their ability to block the binding of erythrocytes to transfected Cos cells expressing on their surface region II of the Duffy-binding ligands. The binding site on the human Duffy antigen used by both the P. vivax and P. knowlesi ligands maps to a 35-amino acid region. A 34-amino acid peptide from the equivalent region of the rhesus Duffy antigen blocked the binding of P. vivax to human erythrocytes, although the P. vivax ligand expressed on Cos cells does not bind rhesus erythrocytes. The binding of the rhesus peptide, but not the rhesus erythrocyte, to the P. vivax ligand was explained by interference of carbohydrate with the binding process. Rhesus erythrocytes, treated with N-glycanase, bound specifically to P. vivax region II. Thus, the interaction of P. vivax ligand with human and rhesus erythrocytes appears to be mediated by a peptide-peptide interaction. Glycosylation of the rhesus Duffy antigen appears to block binding of the P. vivax ligand to rhesus erythrocytes.
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Li, Huiqing, Jing Wei, Youming Dong, and Zhiyue Yu. "Interaction between 2-(p-toluidino)-6-naphthalenesulfonic acid sodium salt (TNS) and β-lactoglobulin." Canadian Journal of Chemistry 94, no. 8 (August 2016): 680–86. http://dx.doi.org/10.1139/cjc-2015-0450.
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The major bovine milk protein β-lactoglobulin (β-LG), a member of the lipocalin superfamily, can bind a wide range of ligands and act as a transporter. In the present study, the combination of the hydrophobic molecule 2-(p-toluidino)-6-naphthalenesulfonic acid sodium salt (TNS) with β-LG was analyzed using fluorescence spectroscopy and AutoDock modeling to discern the major binding sites of the protein and to determine the capacity of other small ligands to bind with β-LG by utilizing TNS as a reference. The experimental data indicate that in a neutral pH environment, TNS is located in the hydrophobic domain of the protein, 2.5 nm away from the Trp19 residues of β-LG. The binding constant of the small molecule to β-LG is (3.30 ± 0.32) × 106 (mol L–1)−1. An interaction model between the ligand and β-LG was developed, and AutoDock modeling also demonstrates that the ligand is located in the central hydrophobic calyx of β-LG within the regions covered by the Förster radius of the Trp19–ligand pair. Although the interaction between the ligand and β-LG is affected by increasing ion strength, pH change, and heat treatment, the complex is maintained until the secondary structure of β-LG is destroyed. Additionally, the ligand binding stabilizes the folding of β-LG. The binding constants of sodium dodecyl sulfate (SDS) and sodium dodecylbenzene sulfonate (SDBS) to β-LG were obtained using competitive ligand binding measurements. With a sensitive fluorescence signal and stable complex, the ligand could be utilized as a reference to detect the binding of other small ligands to β-LG.
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Sencanski, Milan, Milovan Ivanovic, Sonja Vuckovic, and Ljiljana Dosen-Micovic. "Modeling the ligand specific μ- and δ-opioid receptor conformations." Journal of the Serbian Chemical Society 76, no. 9 (2011): 1247–62. http://dx.doi.org/10.2298/jsc110120110s.
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An automated docking procedure was applied to study the binding of a series of ?- and ?-selective ligands to ligand-specific ?- and ?-opioid receptor models. Short-time molecular dynamic simulations were used to obtain ligand-specific ?- and ?-opioid receptors from arbitrarily chosen models of the active form of these receptors. The quality of receptor model depended on the molecular volume of the ligand in the receptor-ligand complex used in the molecular dynamic simulations. Within a series of ligands of similar size (volume), the results of ligand docking to the obtained ligand-specific receptor conformation were in agreement with point mutation studies. The correlation of the calculated and the experimentally determined binding energies was improved in relation to the initial receptor conformation.
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Zlatovic, Mario, Vladimir Sukalovic, Sladjana Kostic-Rajacic, Deana Andric, and Goran Roglic. "Influence of N-1 substituent properties on binding affinities of arylpiperazines to the binding site of 5-HT1A receptor." Journal of the Serbian Chemical Society 71, no. 11 (2006): 1125–35. http://dx.doi.org/10.2298/jsc0611125z.
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Serotonin receptors (5-HTRs), especially the 5-HT1A subtype, have been the subject of intensive research for the past decade, due to their function in human physiology. Several structurally different classes of ligands are known to bind to the 5-HT1A receptor, but arylpiperazine derivatives are among the most important ligands. In the work, docking analyses were used to explain the binding affinities of a series of ligands with different N-1 substituent. All ligands had in common the arylpiperazine structure, while the N-1 subsistent was modified to investigate the influence of ligand structure on its binding affinity. The shape and size, as well as the rigidity of the subsistents were altered to investigate the possible effects on the formation of the receptor - ligand complex.
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Kappel, Kalli, Yinglong Miao, and J. Andrew McCammon. "Accelerated molecular dynamics simulations of ligand binding to a muscarinic G-protein-coupled receptor." Quarterly Reviews of Biophysics 48, no. 4 (July 16, 2015): 479–87. http://dx.doi.org/10.1017/s0033583515000153.
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AbstractElucidating the detailed process of ligand binding to a receptor is pharmaceutically important for identifying druggable binding sites. With the ability to provide atomistic detail, computational methods are well poised to study these processes. Here, accelerated molecular dynamics (aMD) is proposed to simulate processes of ligand binding to a G-protein-coupled receptor (GPCR), in this case the M3 muscarinic receptor, which is a target for treating many human diseases, including cancer, diabetes and obesity. Long-timescale aMD simulations were performed to observe the binding of three chemically diverse ligand molecules: antagonist tiotropium (TTP), partial agonist arecoline (ARc) and full agonist acetylcholine (ACh). In comparison with earlier microsecond-timescale conventional MD simulations, aMD greatly accelerated the binding of ACh to the receptor orthosteric ligand-binding site and the binding of TTP to an extracellular vestibule. Further aMD simulations also captured binding of ARc to the receptor orthosteric site. Additionally, all three ligands were observed to bind in the extracellular vestibule during their binding pathways, suggesting that it is a metastable binding site. This study demonstrates the applicability of aMD to protein–ligand binding, especially the drug recognition of GPCRs.
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Chen, Jake Zheng, William Bret Church, Karine Bastard, Anthony P. Duff, and Thomas Balle. "Binding and Dynamics Demonstrate the Destabilization of Ligand Binding for the S688Y Mutation in the NMDA Receptor GluN1 Subunit." Molecules 28, no. 10 (May 15, 2023): 4108. http://dx.doi.org/10.3390/molecules28104108.
Full textAbstract:
Encephalopathies are brain dysfunctions that lead to cognitive, sensory, and motor development impairments. Recently, the identification of several mutations within the N-methyl-D-aspartate receptor (NMDAR) have been identified as significant in the etiology of this group of conditions. However, a complete understanding of the underlying molecular mechanism and changes to the receptor due to these mutations has been elusive. We studied the molecular mechanisms by which one of the first mutations within the NMDAR GluN1 ligand binding domain, Ser688Tyr, causes encephalopathies. We performed molecular docking, randomly seeded molecular dynamics simulations, and binding free energy calculations to determine the behavior of the two major co-agonists: glycine and D-serine, in both the wild-type and S688Y receptors. We observed that the Ser688Tyr mutation leads to the instability of both ligands within the ligand binding site due to structural changes associated with the mutation. The binding free energy for both ligands was significantly more unfavorable in the mutated receptor. These results explain previously observed in vitro electrophysiological data and provide detailed aspects of ligand association and its effects on receptor activity. Our study provides valuable insight into the consequences of mutations within the NMDAR GluN1 ligand binding domain.
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Komiyama, Yusuke, Masaki Banno, Kokoro Ueki, Gul Saad, and Kentaro Shimizu. "Automatic generation of bioinformatics tools for predicting protein–ligand binding sites." Bioinformatics 32, no. 6 (November 5, 2015): 901–7. http://dx.doi.org/10.1093/bioinformatics/btv593.
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Abstract Motivation: Predictive tools that model protein–ligand binding on demand are needed to promote ligand research in an innovative drug-design environment. However, it takes considerable time and effort to develop predictive tools that can be applied to individual ligands. An automated production pipeline that can rapidly and efficiently develop user-friendly protein–ligand binding predictive tools would be useful. Results: We developed a system for automatically generating protein–ligand binding predictions. Implementation of this system in a pipeline of Semantic Web technique-based web tools will allow users to specify a ligand and receive the tool within 0.5–1 day. We demonstrated high prediction accuracy for three machine learning algorithms and eight ligands. Availability and implementation: The source code and web application are freely available for download at http://utprot.net. They are implemented in Python and supported on Linux. Contact: shimizu@bi.a.u-tokyo.ac.jp Supplementary information: Supplementary data are available at Bioinformatics online.
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Silverman, D. H., J. M. Krueger, and M. L. Karnovsky. "Specific binding sites for muramyl peptides on murine macrophages." Journal of Immunology 136, no. 6 (March 15, 1986): 2195–201. http://dx.doi.org/10.4049/jimmunol.136.6.2195.
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Abstract Two radiolabeled (125I) muramyl peptide derivatives of high specific activity were prepared: a tripeptide with an iodinated C-terminal tyrosine methyl ester (Ligand I), and a muramyl tripeptide with a C-terminal lysine derivatized with Bolton-Hunter reagent (Ligand II). These were used to characterize binding of muramyl peptides to monolayers of murine macrophages. Saturable high-affinity binding to resident, caseinate-elicited, and Listeria-activated peritoneal cells was observed with both radioligands. Binding affinities varied with the state of activation of the macrophages, and KD values ranged from 48 +/- 33 pM (for resident macrophages, Ligand I) to 1020 +/- 90 pM (for activated macrophages, Ligand II). Specific binding sites were also found on a macrophage-derived cell line. The ability of several unlabeled muramyl peptides to compete with Ligands I and II for their binding sites was tested. Competition was stereospecific and correlated with known biological activities of these compounds (i.e., immunoadjuvanticity, pyrogenicity, and somnogenicity). The sites identified here for Ligands I and II may mediate some of the effects that muramyl peptides have previously been demonstrated to have on macrophages.
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Katzenellenbogen, J. A., and R. Muthyala. "Interactions of exogenous endocrine active substances with nuclear receptors." Pure and Applied Chemistry 75, no. 11-12 (January 1, 2003): 1797–817. http://dx.doi.org/10.1351/pac200375111797.
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Nuclear receptors function as ligand-regulated transcription factors and modulate the expression of sets of genes in response to varying concentrations of ligands. The ligand modulators can be endogenous metabolites that function as hormones, or they can be exogenous substances, such as pharmaceutical agents or environmental substances of natural or man-made origin, which in some cases can cause endocrine disruption. Ligands modulate nuclear receptor activity by binding to their ligand-binding domains and stabilizing conformations that lead either to transcriptional activation or repression. The ligand-binding pocket is somewhat flexible, and binding affinities can be measured over a 10-million-fold range (i.e., with equilibrium dissociation constant values ranging from ca. 0.01 nM to 100 μM). Thus, it is not surprising that by binding a large variety of structures, some nuclear receptors can appear to be promiscuous; however, when affinity is considered, the binding patterns are more restricted. The spectrum of ligands that bind to the estrogen receptor has been most thoroughly investigated. Those from natural sources include natural products in food, such as soy isoflavones and whole grain lignans, as well as microbial products and components from wood. Aside from pharmaceuticals, man-made estrogen ligands can be found in industrial products, such as alkyl phenols from nonionic detergents, bisphenols from plastics, indicator dye impurities, polymer chemicals, and chlorinated aromatics and pesticides. Exogenous ligands are also known for the androgen and progesterone receptors. While it is possible that endocrine disruption can result from exogenous chemicals acting directly as ligands for the nuclear receptors, endocrine disruption needs to be considered in the broader context; thus, compounds also need to be assessed for their effects at other levels, such as on endogenous hormone production, transport, metabolism, and clearance, and at points in signal transduction cascades that are beyond the ligand-receptor interaction.
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Tu, L., A. Chen, M. D. Delahunty, K. L. Moore, S. R. Watson, R. P. McEver, and T. F. Tedder. "L-selectin binds to P-selectin glycoprotein ligand-1 on leukocytes: interactions between the lectin, epidermal growth factor, and consensus repeat domains of the selectins determine ligand binding specificity." Journal of Immunology 157, no. 9 (November 1, 1996): 3995–4004. http://dx.doi.org/10.4049/jimmunol.157.9.3995.
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Abstract The selectins mediate cellular interactions by binding carbohydrate determinants present on a limited number of glycoprotein ligands. L-selectin binds multiple ligands expressed on endothelial cells, while P-selectin interacts exclusively with P-selectin glycoprotein ligand-1 (PSGL-1) on leukocytes. In this study, L-selectin was shown to bind leukocytes through the P-selectin ligand, PSGL-1, although at lower levels than P-selectin. L-selectin binding to PSGL-1 is specific since it was blocked by Abs to L-selectin or PSGL-1, required appropriate glycosylation of PSGL-1, and was Ca2+ dependent. The contributions of the extracellular domains of the selectins to ligand binding was assessed using a panel of chimeric selectins created by exchange of domains between L-selectin and P- or E-selectin. The lectin and epidermal growth factor domains of L- and P-selectin contributed significantly to binding through similar, if not identical, regions of PSGL-1. The different chimeric selectins revealed that the lectin domain was the dominant determinant for ligand binding, while cooperative interactions between the lectin, epidermal growth factor, and short consensus repeat domains of the selectins also modified ligand binding specificity. L-selectin binding to PSGL-1 expressed by leukocytes may mediate neutrophil rolling on stationary leukocytes bound to cytokine-induced endothelial cells, which was previously reported to be a L-selectin-dependent process.
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Rosendal, J., P. Ertbjerg, and J. Knudsen. "Characterization of ligand binding to acyl-CoA-binding protein." Biochemical Journal 290, no. 2 (March 1, 1993): 321–26. http://dx.doi.org/10.1042/bj2900321.
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Ligand binding to recombinant bovine acyl-CoA-binding protein (rACBP) was examined using a Lipidex 1000 competition assay and an e.p.r. spectroscopy displacement assay. Of all putative ligands tested, rACBP exhibited a high binding affinity only for acyl-CoA esters. No alternative ligands could be found in rat liver fractions purified on an affinity of column on which ACBP was coupled to Sepharose 4B. E.p.r. data indicate that both the acyl chain and the CoA head group of acyl-CoA are involved in binding and that the 3′-phosphate group on the ribose moiety of acyl-CoA esters plays a crucial role in the binding of acyl-CoA to ACBP. E.p.r. competition binding studies show that the binding affinity of acyl-CoA esters for rACBP is strongly dependent on the length of the acyl chain with a clear preference for acyl-CoA esters with 14-22 carbon atoms in the acyl chain. No correlation between the number of double bonds in the acyl chain and the binding affinity was observed. The experimental results strongly indicate that ACBP specifically binds long-chain acyl-CoA esters with a very high affinity, results that indicate that ACBP is likely to be involved in the intracellular transport and pool formation of these compounds.
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Schaaf, Marcel J. M., and John A. Cidlowski. "Molecular Determinants of Glucocorticoid Receptor Mobility in Living Cells: the Importance of Ligand Affinity." Molecular and Cellular Biology 23, no. 6 (March 15, 2003): 1922–34. http://dx.doi.org/10.1128/mcb.23.6.1922-1934.2003.
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ABSTRACT The actions of glucocorticoids are mediated by the glucocorticoid receptor (GR), which is activated upon ligand binding, and can alter the expression of target genes either by transrepression or transactivation. We have applied FRAP (fluorescence recovery after photobleaching) to quantitatively assess the mobility of the yellow fluorescent protein (YFP)-tagged human GR α-isoform (hGRα) in the nucleus of transiently transfected COS-1 cells and to elucidate determinants of its mobility. Addition of the high-affinity agonist dexamethasone markedly decreases the mobility of the receptor in a concentration-dependent manner, whereas low-affinity ligands like corticosterone decrease the mobility to a much lesser extent. Analysis of other hGRα ligands differing in affinity suggests that it is the affinity of the ligand that is a major determinant of the decrease in mobility. Similar results were observed for two hGRα antagonists, the low-affinity antagonist ZK98299 and the high-affinity antagonist RU486. The effect of ligand affinity on mobility was confirmed with the hGRα mutant Q642V, which has an altered affinity for triamcinolone acetonide, dexamethasone, and corticosterone. Analysis of hGRα deletion mutants indicates that both the DNA-binding domain and the ligand-binding domain of the receptor are required for a maximal ligand-induced decrease in receptor mobility. Interestingly, the mobility of transfected hGRα differs among cell types. Finally, the proteasome inhibitor MG132 immobilizes a subpopulation of unliganded receptors, via a mechanism requiring the DNA-binding domain and the N-terminal part of the ligand-binding domain. Ligand binding makes the GR resistant to the immobilizing effect of MG132, and this effect depends on the affinity of the ligand. Our data suggest that ligand binding induces a conformational change of the receptor which is dependent on the affinity of the ligand. This altered conformation decreases the mobility of the receptor, probably by targeting the receptor to relatively immobile nuclear domains with which it transiently associates. In addition, this conformational change blocks immobilization of the receptor by MG132.
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Miao, Yinglong, Apurba Bhattarai, and Jinan Wang. "Ligand Gaussian Accelerated Molecular Dynamics (LiGaMD): Characterization of Ligand Binding Thermodynamics and Kinetics." Journal of Chemical Theory and Computation 16, no. 9 (July 21, 2020): 5526–47. http://dx.doi.org/10.1021/acs.jctc.0c00395.
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Preisler-Mashek, Mara T., Natalia Solodin, Bethany L. Stark, Michael K. Tyriver, and Elaine T. Alarid. "Ligand-specific regulation of proteasome-mediated proteolysis of estrogen receptor-α." American Journal of Physiology-Endocrinology and Metabolism 282, no. 4 (April 1, 2002): E891—E898. http://dx.doi.org/10.1152/ajpendo.00353.2001.
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Proteasome-mediated proteolysis modulates the cellular concentration of estrogen receptor-α (ERα) and is induced by treatment of cells with 17β-estradiol. Herein, we show that multiple receptor agonists, including 17α-estradiol and estriol as well as the antagonist ICI-182780, stimulate proteasome-dependent proteolysis of ERα in a process that requires ligand binding to the receptor. Proteolysis of receptor depends on ligand concentration, and there exists a direct correlation between ligand-binding affinity and the half-maximal dose of ligand required to stimulate receptor degradation. Furthermore, introduction of a point mutation into the receptor ligand-binding pocket yields a stable receptor resistant to proteolysis. Interestingly, although all ligands stimulate receptor degradation, the extent to which overall ER levels are affected varies with each ligand and is not related to ligand-binding affinity or activation of transcription. These results demonstrate ligand-specific regulation of ERα proteolysis, and they introduce the concept that cellular receptor concentration is governed not only at the level of induction of proteolysis but also by the efficiency with which the receptor is degraded.
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Yoshikawa, Chisato, Hiroaki Ishida, Nami Ohashi, and Toshimasa Itoh. "Synthesis of a Coumarin-Based PPARγ Fluorescence Probe for Competitive Binding Assay." International Journal of Molecular Sciences 22, no. 8 (April 14, 2021): 4034. http://dx.doi.org/10.3390/ijms22084034.
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Peroxisome proliferator-activated receptor γ (PPARγ) is a molecular target of metabolic syndrome and inflammatory disease. PPARγ is an important nuclear receptor and numerous PPARγ ligands were developed to date; thus, efficient assay methods are important. Here, we investigated the incorporation of 7-diethylamino coumarin into the PPARγ agonist rosiglitazone and used the compound in a binding assay for PPARγ. PPARγ-ligand-incorporated 7-methoxycoumarin, 1, showed weak fluorescence intensity in a previous report. We synthesized PPARγ-ligand-incorporating coumarin, 2, in this report, and it enhanced the fluorescence intensity. The PPARγ ligand 2 maintained the rosiglitazone activity. The obtained partial agonist 6 appeared to act through a novel mechanism. The fluorescence intensity of 2 and 6 increased by binding to the ligand binding domain (LBD) of PPARγ and the affinity of reported PPARγ ligands were evaluated using the probe.
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Kim, Hye Yeon, Ae Nim Pae, Yeon Joo Lee, Joon Kyu Park, Dae Sung Kim, Kwang Yeon Hwang, Myeong-Hee Yu, and Eunice EunKyeong Kim. "Structural Comparison of Ligand-Binding Domains in Estrogen-Related Receptors." Key Engineering Materials 277-279 (January 2005): 107–12. http://dx.doi.org/10.4028/www.scientific.net/kem.277-279.107.
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Estrogen-related receptors (ERRs), orphan nuclear receptors, share a significant amino acid sequence homology with estrogen receptors (ERs), yet their ligands do not respond in the same manner. In fact, some of the ligands that are known as agonists of ERs show antagonistic effect in ERRs. Accordingly, the current study investigated the structures of the ligand-binding domains using homology model building and docking studies. The results showed clear differences between the ligand-binding pockets of ERRs and ERs, thereby providing structural insights into the activities related to the ligands.
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Lee, Simon, Clare Faux, Jennifer Nixon, Daniel Alete, John Chilton, Muhamed Hawadle, and Andrew W. Stoker. "Dimerization of Protein Tyrosine Phosphatase σ Governs both Ligand Binding and Isoform Specificity." Molecular and Cellular Biology 27, no. 5 (December 18, 2006): 1795–808. http://dx.doi.org/10.1128/mcb.00535-06.
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ABSTRACT Signaling through receptor protein tyrosine phosphatases (RPTPs) can influence diverse processes, including axon development, lymphocyte activation, and cell motility. The molecular regulation of these enzymes, however, is still poorly understood. In particular, it is not known if, or how, the dimerization state of RPTPs is related to the binding of extracellular ligands. Protein tyrosine phosphatase σ (PTPσ) is an RPTP with major isoforms that differ in their complements of fibronectin type III domains and in their ligand-binding specificities. In this study, we show that PTPσ forms homodimers in the cell, interacting at least in part through the transmembrane region. Using this knowledge, we provide the first evidence that PTPσ ectodomains must be presented as dimers in order to bind heterophilic ligands. We also provide evidence of how alternative use of fibronectin type III domain complements in two major isoforms of PTPσ can alter the ligand binding specificities of PTPσ ectodomains. The data suggest that the alternative domains function largely to change the rotational conformations of the amino-terminal ligand binding sites of the ectodomain dimers, thus imparting novel ligand binding properties. These findings have important implications for our understanding of how heterophilic ligands interact with, and potentially regulate, RPTPs.
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Mikolajek, H., P. Mangione, S. P. Wood, and M. B. Pepys. "Ligand binding to pentraxins." Acta Crystallographica Section A Foundations of Crystallography 64, a1 (August 23, 2008): C316. http://dx.doi.org/10.1107/s0108767308089885.
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Di Cera, Enrico. "Mechanisms of ligand binding." Biophysics Reviews 1, no. 1 (December 2020): 011303. http://dx.doi.org/10.1063/5.0020997.
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Kiger, Laurent, Julien Uzan, Sylvia Dewilde, Thorsten Burmester, Thomas Hankeln, Luc Moens, Djemel Hamdane, Veronique Baudin-Creuza, and Michael Marden. "Neuroglobin Ligand Binding Kinetics." IUBMB Life 56, no. 11 (November 2004): 709–19. http://dx.doi.org/10.1080/15216540500037711.
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Bligh, P. H. "Ligand binding — A primer." Biochemical Education 16, no. 4 (October 1988): 186–95. http://dx.doi.org/10.1016/0307-4412(88)90115-x.
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Reiter, Johannes, and Irving R. Epstein. "Cooperative ligand-lattice binding." Biophysical Chemistry 33, no. 1 (March 1989): 1–9. http://dx.doi.org/10.1016/0301-4622(89)80001-8.
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