Abstract
A new homology model of the GABA binding site of the GABA(C) receptor was built. Natural agonist GABA and antagonist TPMPA were docked into the receptor and molecular dynamics simulation of the complexes was performed to clarify binding poses of the ligands. It was shown that orientation of the ligand is defined by salt bridges between the ligand and the arginine (Arg104) and glutamate residues (Glu194 and Glu196) of the binding site. Different behavior and binding poses for agonist and antagonist was demonstrated by molecular dynamics simulation along with differential movement of the loop C during agonist and antagonist binding. Binding orientations of the ligands revealed that main binding forces in the GABA binding site should be electrostatic ones.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Arginine
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Binding Sites
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Computer Simulation
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GABA Agonists / chemistry*
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GABA Agonists / metabolism
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GABA Antagonists / chemistry*
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GABA Antagonists / metabolism
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Glutamic Acid
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Humans
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Ligands
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Models, Molecular*
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Molecular Sequence Data
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Phosphinic Acids / chemistry*
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Phosphinic Acids / metabolism
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Protein Conformation
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Pyridines / chemistry*
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Pyridines / metabolism
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Receptors, GABA / chemistry*
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Receptors, GABA / metabolism
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Static Electricity
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Tyrosine
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gamma-Aminobutyric Acid / chemistry*
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gamma-Aminobutyric Acid / metabolism
Substances
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(1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid
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GABA Agonists
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GABA Antagonists
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Ligands
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Phosphinic Acids
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Pyridines
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Receptors, GABA
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rho1 GABA(C) receptor, human
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Glutamic Acid
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Tyrosine
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gamma-Aminobutyric Acid
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Arginine