6cm4

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Structure of the D2 Dopamine Receptor Bound to the Atypical Antipsychotic Drug Risperidone

Structural highlights

6cm4 is a 1 chain structure with sequence from Escherichia virus T4 and Homo sapiens. This structure supersedes the now removed PDB entry 6c38. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.867Å
Ligands:8NU, OLA, PEG
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

ENLYS_BPT4 Endolysin with lysozyme activity that degrades host peptidoglycans and participates with the holin and spanin proteins in the sequential events which lead to the programmed host cell lysis releasing the mature viral particles. Once the holin has permeabilized the host cell membrane, the endolysin can reach the periplasm and break down the peptidoglycan layer.[1] DRD2_HUMAN Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase (By similarity).[2] [3]

Publication Abstract from PubMed

Dopamine is a neurotransmitter that has been implicated in processes as diverse as reward, addiction, control of coordinated movement, metabolism and hormonal secretion. Correspondingly, dysregulation of the dopaminergic system has been implicated in diseases such as schizophrenia, Parkinson's disease, depression, attention deficit hyperactivity disorder, nausea and vomiting, among others. Dopamine's actions are mediated by a family of five G-protein coupled receptors (GPCRs) (viz. D1, D2, D3, D4 and D5)(1). The D2 dopamine receptor (DRD2) is the primary target for both typical(2) and atypical(3,4) antipsychotic drugs, and for Parkinson's disease drugs. Unfortunately, many drugs targeting DRD2 frequently cause serious and potentially life-threatening side effects due to promiscuous activities against related receptors(4,5). Accordingly, a molecular understanding of DRD2 structure and function could provide a template for the design of safer and more effective medications. Here we provide the crystal structure of DRD2 in complex with the widely prescribed atypical antipsychotic drug risperidone. The DRD2-risperidone structure reveals an unexpected mode of antipsychotic drug binding to dopamine receptors, and illuminates structural determinants essential for the actions of risperidone and related drugs at DRD2.

Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone.,Wang S, Che T, Levit A, Shoichet BK, Wacker D, Roth BL Nature. 2018 Jan 24. pii: nature25758. doi: 10.1038/nature25758. PMID:29466326[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
25 reviews cite this structure
Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia.
Martel et al. (2020)
24 more
72 other articles
No citations found

See Also

References

  1. ↑ Moussa SH, Kuznetsov V, Tran TA, Sacchettini JC, Young R. Protein determinants of phage T4 lysis inhibition. Protein Sci. 2012 Apr;21(4):571-82. doi: 10.1002/pro.2042. Epub 2012 Mar 2. PMID:22389108 doi:http://dx.doi.org/10.1002/pro.2042
  2. ↑ 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
  3. ↑ 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
  4. ↑ Wang S, Che T, Levit A, Shoichet BK, Wacker D, Roth BL. Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone. Nature. 2018 Jan 24. pii: nature25758. doi: 10.1038/nature25758. PMID:29466326 doi:http://dx.doi.org/10.1038/nature25758

Contents


PDB ID 6cm4

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