Document Detail


Molecular dynamics of dopamine at the D2 receptor.
MedLine Citation:
PMID:  1910173     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A three-dimensional model of the dopamine D2 receptor, assumed to be a target of antipsychotic drug action, was constructed from its amino acid sequence. The model was based on structural similarities within the super-family of guanine nucleotide-binding regulatory (G) protein-coupled neuroreceptors and has seven alpha-helical transmembrane segments that form a central core with a putative ligand-binding site. The space between two residues postulated to be involved in agonist binding, Asp-80 and Asn-390, perfectly accommodated an anti-dopamine molecule. Molecular electrostatic potentials were mainly negative on the synaptic side of the receptor model and around aspartate residues lining the central core and positive in the cytoplasmic domains. The docking of dopamine into a postulated binding site was examined by molecular dynamics simulation. The protonated amino group became oriented toward negatively charged aspartate residues in helix 2 and helix 3, whereas the dopamine molecule fluctuated rapidly between different anti and gauche conformations during the simulation. The receptor model suggests that protonated ligands are attracted to the binding site by electrostatic forces and that protonated agonists may induce conformational changes in the receptor, leading to G-protein activation, by increasing the electrostatic potentials near Asp-80.
Authors:
S G Dahl; O Edvardsen; I Sylte
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  88     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  1991 Sep 
Date Detail:
Created Date:  1991-10-21     Completed Date:  1991-10-21     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  8111-5     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, Institute of Medical Biology, University of Tromsø, Norway.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Animals
Binding Sites
Computer Simulation
Dopamine / chemistry,  metabolism*
GTP-Binding Proteins / metabolism
Macromolecular Substances
Membrane Proteins / chemistry,  metabolism
Models, Molecular
Molecular Sequence Data
Protein Conformation
Rats
Receptors, Dopamine / chemistry,  metabolism*
Sequence Alignment
Solubility
Chemical
Reg. No./Substance:
0/Macromolecular Substances; 0/Membrane Proteins; 0/Receptors, Dopamine; EC 3.6.1.-/GTP-Binding Proteins
Comments/Corrections

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