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Structure paper

TitleStructure-based design of an opioid receptor modulator for enhanced morphine analgesia.
Journal, issue, pagesSci Adv, Vol. 12, Issue 7, Page eaea9832, Year 2026
Publish dateFeb 13, 2026
AuthorsYue Wang / Ping Luo / Haiyan Xu / Li Zhan / Kensuke Sakamoto / Mingyu Li / Jing Wang / Xi-Ping Huang / Jianhui Zhou / Tao Liu / Yanrui Suo / Wenjia Fan / Xinheng He / Youwei Xu / Yongjie Cai / Chao Wang / Yuxi Zhao / Antao Dai / Yali Lai / Qingning Yuan / Wen Hu / Kai Wu / Dehua Yang / Xi Cheng / Xiaojie Lu / Brian Krumm / Terry Kenakin / Jian Zhang / Bryan L Roth / Zhaobing Gao / H Eric Xu / Youwen Zhuang /
PubMed AbstractThe 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 ...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.
External linksSci Adv / PubMed:41671375 / PubMed Central
MethodsEM (single particle)
Resolution2.65 - 2.97 Å
Structure data

39009

8y71

EMDB-39009, PDB-8y71:
positive allosteric modulator(BMS986187)-bound delta-opioid receptor-Gi complex
Method: EM (single particle) / Resolution: 2.97 Å

39010

8y72

EMDB-39010, PDB-8y72:
positive allosteric modulator(BMS986122)-bound mu-opioid receptor-Gi complex
Method: EM (single particle) / Resolution: 2.65 Å

39011

8y73

EMDB-39011, PDB-8y73:
positive allosteric modulator(MPAM-15)-bound mu-opioid receptor-Gi complex
Method: EM (single particle) / Resolution: 2.84 Å

62849

9l60

EMDB-62849, PDB-9l60:
Gi-bound kappa opioid receptor in complex with dynorphin and positive allosteric modulator MPAM-15
Method: EM (single particle) / Resolution: 2.9 Å

Chemicals

PDB-1d6b:
SOLUTION STRUCTURE OF DEFENSIN-LIKE PEPTIDE-2 (DLP-2) FROM PLATYPUS VENOM

PDB-1d6f:
CHALCONE SYNTHASE C164A MUTANT

ChemComp-CLR:
CHOLESTEROL


ChemComp, No image

ChemComp-VV9:
Unknown entry

PDB-1d6c:
Unknown entry

Source
  • homo sapiens (human)
  • rattus norvegicus (Norway rat)
  • bos taurus (domestic cattle)
  • synthetic construct (others)
KeywordsMEMBRANE PROTEIN / positive allosteric modulator / BMS986187 / delta-opioid receptor / allosteric agonism / allosteric opioid analgesics / BMS986122 / mu-opioid receptor / MPAM-15 / Complex / GPCR

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