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

Aashish Manglik; Andrew C. Kruse; Tong Sun Kobilka; Foon Sun Thian; Jesper M. Mathiesen; Roger K. Sunahara; Leonardo Pardo; William I. Weis; Brian K. Kobilka; Sébastien Granier

doi:10.1038/nature10954

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

Aashish Manglik, Andrew C. Kruse, Tong Sun Kobilka, Foon Sun Thian, Jesper M. Mathiesen, Roger K. Sunahara, Leonardo Pardo, William I. Weis, Brian K. Kobilka, Sébastien Granier^*

^*Corresponding author for this work

925 Citations (Scopus)

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 2.8Å 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.

Original language	English
Journal	Nature
Volume	485
Issue number	7398
Pages (from-to)	321-326
Number of pages	6
ISSN	0028-0836
DOIs	https://doi.org/10.1038/nature10954
Publication status	Published - 17 May 2012

Access to Document

10.1038/nature10954

Cite this

@article{45881b46516a46399feb2dd0683b58f9,

title = "Crystal structure of the μ-opioid receptor bound to a morphinan antagonist",

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{\AA} 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.",

author = "Aashish Manglik and Kruse, {Andrew C.} and Kobilka, {Tong Sun} and Thian, {Foon Sun} and Mathiesen, {Jesper M.} and Sunahara, {Roger K.} and Leonardo Pardo and Weis, {William I.} and Kobilka, {Brian K.} and S{\'e}bastien Granier",

year = "2012",

month = may,

day = "17",

doi = "10.1038/nature10954",

language = "English",

volume = "485",

pages = "321--326",

journal = "Nature",

issn = "0028-0836",

publisher = "nature publishing group",

number = "7398",

}

TY - JOUR

T1 - Crystal structure of the μ-opioid receptor bound to a morphinan antagonist

AU - Manglik, Aashish

AU - Kruse, Andrew C.

AU - Kobilka, Tong Sun

AU - Thian, Foon Sun

AU - Mathiesen, Jesper M.

AU - Sunahara, Roger K.

AU - Pardo, Leonardo

AU - Weis, William I.

AU - Kobilka, Brian K.

AU - Granier, Sébastien

PY - 2012/5/17

Y1 - 2012/5/17

N2 - 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 2.8Å 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.

AB - 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 2.8Å 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.

UR - http://www.scopus.com/inward/record.url?scp=84861096654&partnerID=8YFLogxK

U2 - 10.1038/nature10954

DO - 10.1038/nature10954

M3 - Journal article

C2 - 22437502

AN - SCOPUS:84861096654

SN - 0028-0836

VL - 485

SP - 321

EP - 326

JO - Nature

JF - Nature

IS - 7398

ER -

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

Abstract

Access to Document

Other files and links

Fingerprint

Cite this