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Science. 2017 Oct 20;358(6361):381-386. doi: 10.1126/science.aan5468.

D4 dopamine receptor high-resolution structures enable the discovery of selective agonists.

Author information

1
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA. shengunc@email.unc.edu dwacker@email.unc.edu bshoichet@gmail.com bryan_roth@med.unc.edu.
2
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158-2280, USA.
3
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA.
4
Department of Computer Science, Stanford University, CA 94305, USA.
5
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
6
Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA.
7
Biophysics Program, Stanford University, Stanford, CA 94305, USA.
8
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158-2280, USA. shengunc@email.unc.edu dwacker@email.unc.edu bshoichet@gmail.com bryan_roth@med.unc.edu.
9
Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, USA.
10
National Institute of Mental Health Psychoactive Drug Screening Program, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA.

Abstract

Dopamine receptors are implicated in the pathogenesis and treatment of nearly every neuropsychiatric disorder. Although thousands of drugs interact with these receptors, our molecular understanding of dopaminergic drug selectivity and design remains clouded. To illuminate dopamine receptor structure, function, and ligand recognition, we determined crystal structures of the D4 dopamine receptor in its inactive state bound to the antipsychotic drug nemonapride, with resolutions up to 1.95 angstroms. These structures suggest a mechanism for the control of constitutive signaling, and their unusually high resolution enabled a structure-based campaign for new agonists of the D4 dopamine receptor. The ability to efficiently exploit structure for specific probe discovery-rapidly moving from elucidating receptor structure to discovering previously unrecognized, selective agonists-testifies to the power of structure-based approaches.

PMID:
29051383
PMCID:
PMC5856174
DOI:
10.1126/science.aan5468
[Indexed for MEDLINE]
Free PMC Article

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