TY - JOUR
T1 - Structural basis for μ-opioid receptor binding and activation
AU - Serohijos, Adrian W.R.
AU - Yin, Shuangye
AU - Ding, Feng
AU - Gauthier, Josee
AU - Gibson, Dustin G.
AU - Maixner, William
AU - Dokholyan, Nikolay V.
AU - Diatchenko, Luda
N1 - Funding Information:
This work was supported in part by NIH/NIDCR, NIH/NINDS, and NIH/NCRR grants RO1-DE16558 (L.D. and W.M.), UO1-DE017018 (W.M. and L.D.), NS41670 (W.M.), PO1 NS045685 (W.M. and L.D.), R01GM080742 (N.V.D.), the ARRA supplement 3R01GM080742-03S1 (N.V.D.), and research funds from Algynomics Inc. and Molecules in Action, Inc. The authors thank Brian Roth and Vincent Setola and the NIMH Psychoactive Drug Screening Program (PDSP) at UNC for materials and their assistance in performing assays and analyzing data. The authors likewise thank Oskar Laur for the generation of receptor mutants.
PY - 2011/11/9
Y1 - 2011/11/9
N2 - Opioids that stimulate the μ-opioid receptor (MOR1) are the most frequently prescribed and effective analgesics. Here we present a structural model of MOR1. Molecular dynamics simulations show a ligand-dependent increase in the conformational flexibility of the third intracellular loop that couples with the G protein complex. These simulations likewise identified residues that form frequent contacts with ligands. We validated the binding residues using site-directed mutagenesis coupled with radioligand binding and functional assays. The model was used to blindly screen a library of ∼1.2 million compounds. From the 34 compounds predicted to be strong binders, the top three candidates were examined using biochemical assays. One compound showed high efficacy and potency. Post hoc testing revealed this compound to be nalmefene, a potent clinically used antagonist, thus further validating the model. In summary, the MOR1 model provides a tool for elucidating the structural mechanism of ligand-initiated cell signaling and for screening novel analgesics.
AB - Opioids that stimulate the μ-opioid receptor (MOR1) are the most frequently prescribed and effective analgesics. Here we present a structural model of MOR1. Molecular dynamics simulations show a ligand-dependent increase in the conformational flexibility of the third intracellular loop that couples with the G protein complex. These simulations likewise identified residues that form frequent contacts with ligands. We validated the binding residues using site-directed mutagenesis coupled with radioligand binding and functional assays. The model was used to blindly screen a library of ∼1.2 million compounds. From the 34 compounds predicted to be strong binders, the top three candidates were examined using biochemical assays. One compound showed high efficacy and potency. Post hoc testing revealed this compound to be nalmefene, a potent clinically used antagonist, thus further validating the model. In summary, the MOR1 model provides a tool for elucidating the structural mechanism of ligand-initiated cell signaling and for screening novel analgesics.
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U2 - 10.1016/j.str.2011.08.003
DO - 10.1016/j.str.2011.08.003
M3 - Article
C2 - 22078567
AN - SCOPUS:80855156721
SN - 0969-2126
VL - 19
SP - 1683
EP - 1690
JO - Structure
JF - Structure
IS - 11
ER -