TY - JOUR
T1 - D4 dopamine receptor high-resolution structures enable the discovery of selective agonists
AU - Wang, Sheng
AU - Wacker, Daniel
AU - Levit, Anat
AU - Che, Tao
AU - Betz, Robin M.
AU - McCorvy, John D.
AU - Venkatakrishnan, A. J.
AU - Huang, Xi Ping
AU - Dror, Ron O.
AU - Shoichet, Brian K.
AU - Roth, Bryan L.
N1 - Funding Information:
This work was supported by the NIH (grants R01MH112205, U19MH82441, and HHSN-271-2013-00017-C), the Michael Hooker Chair for Protein Therapeutics and Translational Proteomics (to B.L.R.), and the National Institute of General Medical Sciences (NIGMS; grant R35GM122481 to B.K.S.). We thank J. Sondek and S. Endo-Streeter for independent structure quality-control analysis; M. J. Miley and the University of North Carolina macromolecular crystallization core facility supported by the NIH (grant P30CA016086); J. W. Murphy for running FRAP (fluorescence recovery after photobleaching) precrystallization assays; S. Sato for sharing the original DRD4 construct; B. E. Krumm for advice on data processing; and J. Smith, R. Fischetti, and the staff of GM/CA @ APS, supported by the National Cancer Institute (ACB-12002) and NIGMS (AGM-12006). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. Coordinates and structure factors have been deposited in the Protein Data Bank under accession numbers 5WIU (sodium-free) and 5WIV (sodium-bound). UCSF924 and its deactivated negative control UCSF924NC are available as a probe pair from Sigma Millipore (SML2022 and SML2023 for the active and deactivated agonists, respectively).
PY - 2017/10/20
Y1 - 2017/10/20
N2 - Dopamine receptors are implicated in the pathogenesis and treatment of nearly every neuropsychiatric disorder. Although thousands of drugs interactwith 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.
AB - Dopamine receptors are implicated in the pathogenesis and treatment of nearly every neuropsychiatric disorder. Although thousands of drugs interactwith 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.
UR - http://www.scopus.com/inward/record.url?scp=85032508115&partnerID=8YFLogxK
U2 - 10.1126/science.aan5468
DO - 10.1126/science.aan5468
M3 - Article
C2 - 29051383
AN - SCOPUS:85032508115
SN - 0036-8075
VL - 358
SP - 381
EP - 386
JO - Science
JF - Science
IS - 6361
ER -