7dfp

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Human dopamine D2 receptor in complex with spiperone

Structural highlights

7dfp is a 3 chain structure with sequence from Escherichia coli, Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.1Å
Ligands:SIP
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

DRD2_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).

Function

C562_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 PubMed

In 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.

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See Also

References

  1. ↑ Albizu L, Holloway T, Gonzalez-Maeso J, Sealfon SC. Functional crosstalk and heteromerization of serotonin 5-HT2A and dopamine D2 receptors. Neuropharmacology. 2011 Sep;61(4):770-7. doi: 10.1016/j.neuropharm.2011.05.023., Epub 2011 May 27. PMID:21645528 doi:http://dx.doi.org/10.1016/j.neuropharm.2011.05.023
  2. ↑ Johnston CA, Siderovski DP. Structural basis for nucleotide exchange on G alpha i subunits and receptor coupling specificity. Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):2001-6. Epub 2007 Jan 30. PMID:17264214
  3. ↑ 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. Structure of the dopamine D(2) receptor in complex with the antipsychotic drug spiperone. Nat Commun. 2020 Dec 22;11(1):6442. PMID:33353947 doi:10.1038/s41467-020-20221-0

Contents


PDB ID 7dfp

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OCA

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