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PMID: 22437502 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Crystal structure of the µ-opioid receptor bound to a morphinan antagonist.

Nature ·Vol. 485 ·No. 7398 ·2012-03-21 ·Pages 321-6

Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, Pardo L, Weis WI, Kobilka BK, Granier S

Abstract

Opium is one of the world's oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain. These prototypical opioids produce analgesia as well as many undesirable side effects (sedation, apnoea and dependence) by binding to and activating the G-protein-coupled µ-opioid receptor (µ-OR) in the central nervous system. Here we describe the 2.8 Å crystal structure of the mouse µ-OR in complex with an irreversible morphinan antagonist. Compared to the buried binding pocket observed in most G-protein-coupled receptors published so far, the morphinan ligand binds deeply within a large solvent-exposed pocket. Of particular interest, the µ-OR crystallizes as a two-fold symmetrical dimer through a four-helix bundle motif formed by transmembrane segments 5 and 6. These high-resolution insights into opioid receptor structure will enable the application of structure-based approaches to develop better drugs for the management of pain and addiction.

MeSH Terms
Animals Binding Sites Crystallography, X-Ray Ligands Mice Models, Molecular Morphinans/chemistry,metabolism,pharmacology Protein Conformation Protein Multimerization Receptors, Opioid, mu/antagonists & inhibitors,chemistry,metabolism Solvents/chemistry
Chemicals
Ligands Morphinans Receptors, Opioid, mu Solvents
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Manglik Aashish
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA.
Kruse Andrew C
Kobilka Tong Sun
Thian Foon Sun
Mathiesen Jesper M
Sunahara Roger K
Pardo Leonardo
Weis William I
Kobilka Brian K
Granier Sébastien
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature10954
Published
2012-03-21
Epub
2012-00-21
Pages
321-6
Language
English
Region
England
NLM ID
0410462
PMCID
PMC3523197
Subset
IM
Grants
NIDA NIH HHS · DA031418 · United States
NIGMS NIH HHS · R01 GM083118 · United States
NINDS NIH HHS · R01 NS028471 · United States
NINDS NIH HHS · R37 NS028471 · United States
NINDS NIH HHS · NS028471 · United States
NIDA NIH HHS · R21 DA031418 · United States
Databases
PDB
4DKL
Corrections
CommentIn
PMID: 22596150
External Links
PubMed source DOI: 10.1038/nature10954 PMC Full Text View journal details
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