D4 dopamine receptor high-resolution structures enable the discovery of selective agonists. Science 2017 Oct 20;358(6361):381-386
Date
10/21/2017Pubmed ID
29051383Pubmed Central ID
PMC5856174DOI
10.1126/science.aan5468Scopus ID
2-s2.0-85032508115 (requires institutional sign-in at Scopus site) 194 CitationsAbstract
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.
Author List
Wang S, Wacker D, Levit A, Che T, Betz RM, McCorvy JD, Venkatakrishnan AJ, Huang XP, Dror RO, Shoichet BK, Roth BLAuthor
John McCorvy PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Allosteric SiteAntipsychotic Agents
Benzamides
Dopamine Agonists
Humans
Protein Conformation
Receptors, Dopamine D4
Structure-Activity Relationship
