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Science 330 (6007): 1091-1095

Copyright © 2010 by the American Association for the Advancement of Science

Structure of the Human Dopamine D3 Receptor in Complex with a D2/D3 Selective Antagonist

Ellen Y. T. Chien,1 Wei Liu,1 Qiang Zhao,1 Vsevolod Katritch,2 Gye Won Han,1 Michael A. Hanson,3 Lei Shi,4 Amy Hauck Newman,5 Jonathan A. Javitch,6 Vadim Cherezov,1 Raymond C. Stevens1,*

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.

1 Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
2 Skaggs School of Pharmacy and Pharmaceutical Sciences, and San Diego Supercomputer Center, University of California, San Diego, La Jolla, CA 92093, USA.
3 Receptos, 10835 Road to the Cure, Suite 205, San Diego, CA 92121, USA.
4 Department of Physiology and Biophysics and HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, Cornell University, 1300 York Avenue, New York, NY 10021, USA.
5 Medicinal Chemistry Section, National Institute on Drug Abuse–Intramural Research Program, Baltimore, MD 21224, USA.
6 Center for Molecular Recognition and Departments of Psychiatry and Pharmacology, Columbia University College of Physicians and Surgeons, 630 West 168th, New York, NY 10032, USA.

* To whom correspondence should be addressed. E-mail: stevens{at}scripps.edu

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