Ligand binding, signal transduction and allosteric regulation in a model of the transmembrane portion of the serotonin receptor.
Item
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Title
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Ligand binding, signal transduction and allosteric regulation in a model of the transmembrane portion of the serotonin receptor.
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Identifier
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AAI9510742
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identifier
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9510742
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Creator
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Zhang, Daqun.
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Contributor
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Adviser: Harel Weinstein
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Date
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1994
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biology, Molecular | Biophysics, Medical
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Abstract
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A three-dimensional model of the transmembrane portion of scrotonin 5-HT{dollar}\sb2{dollar} receptor is proposed based on various experimental results, physicochemical principles of protein structure prediction, computer graphic modeling and molecular dynamics (MD) simulation. The characteristics of the model are: (1) a shape similar to that reported recently for rhodopsin, another G-protein coupled receptor (GPCR) (1), (2) a helix-helix packing bearing the structural features of GPCRs which are distinctive from that of bacteriorhodospin (2), (3) the helix arrangement satisfying various inferences from experimental results (Chapter IV), (4) a structural response to ligand binding that is consistent with experimental observations of ligand properties and GPCR activation (3-5). A new concept of polarity conserved position is proposed for structural comparison and for modeling specific helix-helix packing in transmembrane helix (TMH) bundles (2). The unique arrangement of TMHs in GPCRs is also identified by integrating available experimental and theoretical study results. Ligand binding and signal transduction of the receptor were studied by MD simulation of interactions between the model and various ligands from different chemical classes with different pharmacological, stereochemical properties, and affinities ranging from 5 to {dollar}>{dollar}10,000 nM. Quantitative correlation between ligand affinities and components of interaction energies were found, and the underlying mechanisms relating to ligand selectivities (4) and allosteric regulation of the receptor (5) were further identified. It is demonstrated that ligand/receptor interactions do not follow the pattern of "lock-and-key". In agreement with features observed from crystal structures of drug/enzyme complexes, different ligands are found to orient differently in the same binding region, and to induce different conformational changes in the receptor. Agonists, but not antagonists, induced specific conformational changes in intracellular portions of TMH5 and 6. These changes are proposed to be the mechanisms of signal transduction through the transmembrane portion of the receptor (3). Conformational changes of the receptor are found to be explainable as rigid-body-like movements of TMHs relative to each other, propagated like a relay of leverage across the helix bundle of the receptor. Supported by the consistent results of mutation experiments and MD simulation, a hydrogen bond network involving TMH1, 2, 3 and 7 are proposed to be the instrument for allosteric regulation of the receptor (5). These results, for the first time, give rise to the mechanisms of signal transduction and allosteric regulation in a GPCR at molecular detail.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
