7dfp
Human dopamine D2 receptor in complex with spiperone
Structural highlights
DiseaseDRD2_HUMAN Myoclonic dystonia 11. The gene represented in this entry may be involved in disease pathogenesis. DRD2 mutations in myoclonic dystonia patients are rare, and their contribution to disease phenotype is unclear (PubMed:10716258). FunctionC562_ECOLX Electron-transport protein of unknown function.DRD2_HUMAN Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase (By similarity).[1] [2] Publication Abstract from PubMedIn addition to the serotonin 5-HT(2A) receptor (5-HT(2A)R), the dopamine D(2) receptor (D(2)R) is a key therapeutic target of antipsychotics for the treatment of schizophrenia. The inactive state structures of D(2)R have been described in complex with the inverse agonists risperidone (D(2)R(ris)) and haloperidol (D(2)R(hal)). Here we describe the structure of human D(2)R in complex with spiperone (D(2)R(spi)). In D(2)R(spi), the conformation of the extracellular loop (ECL) 2, which composes the ligand-binding pocket, was substantially different from those in D(2)R(ris) and D(2)R(hal), demonstrating that ECL2 in D(2)R is highly dynamic. Moreover, D(2)R(spi) exhibited an extended binding pocket to accommodate spiperone's phenyl ring, which probably contributes to the selectivity of spiperone to D(2)R and 5-HT(2A)R. Together with D(2)R(ris) and D(2)R(hal), the structural information of D(2)R(spi) should be of value for designing novel antipsychotics with improved safety and efficacy. Structure of the dopamine D(2) receptor in complex with the antipsychotic drug spiperone.,Im D, Inoue A, Fujiwara T, Nakane T, Yamanaka Y, Uemura T, Mori C, Shiimura Y, Kimura KT, Asada H, Nomura N, Tanaka T, Yamashita A, Nango E, Tono K, Kadji FMN, Aoki J, Iwata S, Shimamura T Nat Commun. 2020 Dec 22;11(1):6442. doi: 10.1038/s41467-020-20221-0. PMID:33353947[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
