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PMID: 21097933 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist.

Science (New York, N.Y.) ·Vol. 330 ·No. 6007 ·2010-11-19 ·Pages 1091-5

Chien EY, Liu W, Zhao Q, Katritch V, Han GW, Hanson MA, Shi L, Newman AH, Javitch JA, Cherezov V, Stevens RC

Abstract

Dopamine modulates movement, cognition, and emotion through activation of dopamine G protein-coupled receptors in the brain. The crystal structure of the human dopamine D3 receptor (D3R) in complex with the small molecule D2R/D3R-specific antagonist eticlopride reveals important features of the ligand binding pocket and extracellular loops. On the intracellular side of the receptor, a locked conformation of the ionic lock and two distinctly different conformations of intracellular loop 2 are observed. Docking of R-22, a D3R-selective antagonist, reveals an extracellular extension of the eticlopride binding site that comprises a second binding pocket for the aryl amide of R-22, which differs between the highly homologous D2R and D3R. This difference provides direction to the design of D3R-selective agents for treating drug abuse and other neuropsychiatric indications.

MeSH Terms
Animals Arginine/chemistry Binding Sites Cell Line Crystallography, X-Ray Dopamine Antagonists/chemistry Dopamine D2 Receptor Antagonists Humans Models, Molecular Protein Conformation Receptors, Dopamine D3/antagonists & inhibitors,chemistry Recombinant Proteins/chemistry Salicylamides/chemistry Spodoptera
Chemicals
Dopamine Antagonists Dopamine D2 Receptor Antagonists Receptors, Dopamine D3 Recombinant Proteins Salicylamides Arginine eticlopride
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Chien Ellen Y T
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Liu Wei
Zhao Qiang
Katritch Vsevolod
Han Gye Won
Hanson Michael A
Shi Lei
Newman Amy Hauck
Javitch Jonathan A
Cherezov Vadim
Stevens Raymond C
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Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
DOI
10.1126/science.1197410
Published
2010-11-19
Pages
1091-5
Language
English
Region
United States
NLM ID
0404511
PMCID
PMC3058422
Subset
IM
Grants
NIGMS NIH HHS · Y1-GM-1104 · United States
NIMH NIH HHS · R01 MH054137-16 · United States
NIMH NIH HHS · R01 MH054137 · United States
NIDA NIH HHS · DA023694 · United States
NIGMS NIH HHS · P50 GM073197-07 · United States
NIDA NIH HHS · R00 DA023694 · United States
NIGMS NIH HHS · GM075915 · United States
NIGMS NIH HHS · U54 GM094618-01 · United States
NIGMS NIH HHS · U54 GM074961 · United States
NIDA NIH HHS · K05 DA022413-05 · United States
NCRR NIH HHS · R21 RR025336-01A1 · United States
NIDA NIH HHS · DA022413 · United States
NCRR NIH HHS · R21 RR025336 · United States
NIDA NIH HHS · R00 DA023694-04 · United States
NIGMS NIH HHS · P50 GM073197 · United States
NIGMS NIH HHS · U54 GM094618 · United States
NIMH NIH HHS · MH54137 · United States
NIDA NIH HHS · K05 DA022413 · United States
NIGMS NIH HHS · U54 GM074961-050001 · United States
Intramural NIH HHS · United States
NIGMS NIH HHS · R01 GM089857 · United States
NCI NIH HHS · Y1-CO-1020 · United States
Databases
PDB
3PBL
External Links
PubMed source DOI: 10.1126/science.1197410 PMC Full Text View journal details
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