8Y73

positive allosteric modulator(MPAM-15)-bound mu-opioid receptor-Gi complex

This is a non-PDB format compatible entry.

Summary for 8Y73

• Entry DOI: 10.2210/pdb8y73/pdb
• EMDB information: 39011
• Related PRD ID: PRD_002308
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (8 entities in total)
• Functional Keywords: positive allosteric modulator, mpam-15, mu-opioid receptor, allosteric agonism, allosteric opioid analgesics, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 160655.50

Authors

Luo, P.,Xu, Y.,Wang, Y.,Zhuang, Y.,Xu, H.E. (deposition date: 2024-02-03, release date: 2025-08-06, Last modification date: 2026-03-11)

Primary citation

Wang, Y.,Luo, P.,Xu, H.,Zhan, L.,Sakamoto, K.,Li, M.,Wang, J.,Huang, X.P.,Zhou, J.,Liu, T.,Suo, Y.,Fan, W.,He, X.,Xu, Y.,Cai, Y.,Wang, C.,Zhao, Y.,Dai, A.,Lai, Y.,Yuan, Q.,Hu, W.,Wu, K.,Yang, D.,Cheng, X.,Lu, X.,Krumm, B.,Kenakin, T.,Zhang, J.,Roth, B.L.,Gao, Z.,Xu, H.E.,Zhuang, Y.
Structure-based design of an opioid receptor modulator for enhanced morphine analgesia.
Sci Adv, 12:eaea9832-eaea9832, 2026

PubMed Abstract: The alarming rates of deaths due to opioid overdose present an urgent need for safer opioid analgesics. Positive allosteric modulators (PAMs) of opioid receptors (ORs) offer a promising approach to enhance opioid efficacy while reducing risks of overdose. In this study, we unveil the selective mechanism of PAM modulation of the OR family through structure elucidation of the δ-opioid receptor and μ-opioid receptor (μOR) bound to orthosteric agonists and PAMs BMS986187 (BMS187) and BMS986122 (BMS122). In addition, we uncovered an unexpected but conserved allosteric site across the transmembrane helices TM2 to TM4 of ORs, occupied by BMS187 but not BMS122. Leveraging these structural insights, we designed 9-(5-(4-chlorophenyl)furan-2-yl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1-xanthene-1,8(2)-dione (MPAM-15), whose αβ cooperativity factor is 33-fold higher than BMS122 and threefold higher than BMS187, indicating markedly stronger positive allosterism. Animal studies demonstrate that MPAM-15 shows excellent brain penetration and enhances morphine-induced antinociception without exacerbating respiratory depression or constipation. Molecular dynamics simulations revealed that MPAM-15 promotes and stabilizes the conformational equilibrium of μOR toward the canonical active state, providing a mechanistic basis for its enhanced allosteric potency. These discoveries substantially advance our understanding of OR allosteric mechanism and pave the way for the structure-based development of allosteric opioid analgesics.

PubMed: 41671375
DOI: 10.1126/sciadv.aea9832

Experimental method

ELECTRON MICROSCOPY (2.84 Å)