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

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 -