9ppq
Locally-refined Mu-Opioid Receptor bound with novel compound 0505 (3-[({[(1P)-1-(3-chlorophenyl)-1H-pyrazol-3-yl]methyl}amino)methyl]phenol)
Structural highlights
FunctionOPRM_HUMAN Receptor for endogenous opioids such as beta-endorphin and endomorphin (PubMed:10529478, PubMed:12589820, PubMed:7891175, PubMed:7905839, PubMed:7957926, PubMed:9689128). Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone (PubMed:10529478, PubMed:10836142, PubMed:12589820, PubMed:19300905, PubMed:7891175, PubMed:7905839, PubMed:7957926, PubMed:9689128). Also activated by enkephalin peptides, such as Met-enkephalin or Met-enkephalin-Arg-Phe, with higher affinity for Met-enkephalin-Arg-Phe (By similarity). Agonist binding to the receptor induces coupling to an inactive GDP-bound heterotrimeric G-protein complex and subsequent exchange of GDP for GTP in the G-protein alpha subunit leading to dissociation of the G-protein complex with the free GTP-bound G-protein alpha and the G-protein beta-gamma dimer activating downstream cellular effectors (PubMed:7905839). The agonist- and cell type-specific activity is predominantly coupled to pertussis toxin-sensitive G(i) and G(o) G alpha proteins, GNAI1, GNAI2, GNAI3 and GNAO1 isoforms Alpha-1 and Alpha-2, and to a lesser extent to pertussis toxin-insensitive G alpha proteins GNAZ and GNA15 (PubMed:12068084). They mediate an array of downstream cellular responses, including inhibition of adenylate cyclase activity and both N-type and L-type calcium channels, activation of inward rectifying potassium channels, mitogen-activated protein kinase (MAPK), phospholipase C (PLC), phosphoinositide/protein kinase (PKC), phosphoinositide 3-kinase (PI3K) and regulation of NF-kappa-B (By similarity). Also couples to adenylate cyclase stimulatory G alpha proteins (By similarity). The selective temporal coupling to G-proteins and subsequent signaling can be regulated by RGSZ proteins, such as RGS9, RGS17 and RGS4 (By similarity). Phosphorylation by members of the GPRK subfamily of Ser/Thr protein kinases and association with beta-arrestins is involved in short-term receptor desensitization (By similarity). Beta-arrestins associate with the GPRK-phosphorylated receptor and uncouple it from the G-protein thus terminating signal transduction (By similarity). The phosphorylated receptor is internalized through endocytosis via clathrin-coated pits which involves beta-arrestins (By similarity). The activation of the ERK pathway occurs either in a G-protein-dependent or a beta-arrestin-dependent manner and is regulated by agonist-specific receptor phosphorylation (By similarity). Acts as a class A G-protein coupled receptor (GPCR) which dissociates from beta-arrestin at or near the plasma membrane and undergoes rapid recycling (By similarity). Receptor down-regulation pathways are varying with the agonist and occur dependent or independent of G-protein coupling (By similarity). Endogenous ligands induce rapid desensitization, endocytosis and recycling (By similarity). Heterooligomerization with other GPCRs can modulate agonist binding, signaling and trafficking properties (By similarity).[UniProtKB:P33535][1] [2] [3] [4] [5] [6] [7] [8] [9] Couples to GNAS and is proposed to be involved in excitatory effects.[10] Does not bind agonists but may act through oligomerization with binding-competent OPRM1 isoforms and reduce their ligand binding activity.[11] Does not bind agonists but may act through oligomerization with binding-competent OPRM1 isoforms and reduce their ligand binding activity.[12] Publication Abstract from PubMedPolypharmacological molecules are attractive for complex illnesses. Here, we explored large library docking for joint activity against target pairs. Retrospectively, as libraries grew, so too did the number of likely dual-activity molecules. In prospective docking of a 900-million molecule library against three target pairs (alpha(2A)/SERT, MOR/SERT, and alpha(2A)/MOR), we sought analgesic compounds. Both the alpha(2A)/SERT and SERT/MOR campaigns led to dual binders with low muM to high nM activities with high hit rates; tetrahydropyridines from the alpha(2A)/SERT campaign were also active against 5-HT(2A). However, even though cryo-EM structures confirmed the docking-predicted poses, optimization struggled to improve potency. Still, in mouse behavioral assays, the most potent alpha(2A)/SERT compound ('z7149) was effective against pain without inducing conditioned place preference, and the molecule had potent antidepression and anxiolytic drug-like behavior, consistent with its SERT/5-HT(2A) activities. This study reveals both advantages and challenges of docking for polypharmacology. Large Library Docking for Polypharmacology.,Wu Y, Vigneron S, Braz J, Srinivasan K, Fink EA, Huang XP, Xu X, Huebner H, Kim JY, Wang J, Pfeiffer T, Sakamoto K, Radchenko DS, Rodriguiz RM, Moroz YS, Irwin JJ, Gmeiner P, Billesboelle C, Roth BL, Basbaum AI, Manglik A, Wetsel WC, Shoichet BK J Med Chem. 2026 Feb 19. doi: 10.1021/acs.jmedchem.5c03810. PMID:41712624[13] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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