Elucidating the active δ-opioid receptor crystal structure with peptide and small-molecule agonists

被引：93

作者：

Claff, Tobias ^{[1
,2
]}

Yu, Jing ^{[1
,3
,4
,5
]}

Blais, Veronique ^{[6
]}

Patel, Nilkanth ^{[7
,8
]}

Martin, Charlotte ^{[9
]}

Wu, Lijie ^{[1
]}

Han, Gye Won ^{[7
,8
]}

Holleran, Brian J. ^{[6
]}

Van der Poorten, Olivier ^{[9
]}

White, Kate L. ^{[7
,8
]}

Hanson, Michael A. ^{[10
]}

Sarret, Philippe ^{[6
]}

Gendron, Louis ^{[6
]}

Cherezov, Vadim ^{[7
,8
]}

Katritch, Vsevolod ^{[7
,8
]}

Ballet, Steven ^{[9
]}

Liu, Zhi-Jie ^{[1
,3
]}

Mueller, Christa E. ^{[2
]}

Stevens, Raymond C. ^{[1
,7
,8
]}

机构：

[1] ShanghaiTech Univ, iHuman Inst, Ren Bldg,393 Middle Huaxia Rd, Shanghai 201210, Peoples R China

[2] Univ Bonn, PharmaCtr Bonn, Pharmaceut Chem 1, Immenburg 4, D-53121 Bonn, Germany

[3] ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China

[4] Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, CAS Ctr Excellence Mol Cell Sci, Shanghai 200031, Peoples R China

[5] Univ Chinese Acad Sci, Beijing 100049, Peoples R China

[6] Univ Sherbrooke, Dept Pharmacol Physiol, Fac Med & Hlth Sci, Inst Pharmacol Sherbrooke,Ctr Rech,CHUS, 3001 12e Ave Nord, Sherbrooke, PQ J1H 5N4, Canada

[7] Univ Southern Calif, USC Michelson Ctr Convergent Biosci, Bridge Inst, Dept Biol Sci, Los Angeles, CA 90089 USA

[8] Univ Southern Calif, USC Michelson Ctr Convergent Biosci, Bridge Inst, Dept Chem, Los Angeles, CA 90089 USA

[9] Vrije Univ Brussel, Dept Chem & Bioengn Sci, Res Grp Organ Chem, Pl Laan 2, B-1050 Brussels, Belgium

[10] GPCR Consortium, San Marcos, CA 92078 USA

来源：

SCIENCE ADVANCES | 2019年 / 5卷 / 11期

关键词：

MEMBRANE-PROTEINS; POTENT; ANALGESIA; LACKING; MODELS; TARGET; BRAIN; STATE;

D O I：

10.1126/sciadv.aax9115

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Selective activation of the.-opioid receptor (DOP) has great potential for the treatment of chronic pain, benefitting from ancillary anxiolytic and antidepressant-like effects. Moreover, DOP agonists show reduced adverse effects as compared to mu-opioid receptor (MOP) agonists that are in the spotlight of the current "opioid crisis." Here, we report the first crystal structures of the DOP in an activated state, in complex with two relevant and structurally diverse agonists: the potent opioid agonist peptide KGCHM07 and the small-molecule agonist DPI-287 at 2.8 and 3.3 angstrom resolution, respectively. Our study identifies key determinants for agonist recognition, receptor activation, and DOP selectivity, revealing crucial differences between both agonist scaffolds. Our findings provide the first investigation into atomic-scale agonist binding at the DOP, supported by site-directed mutagenesis and pharmacological characterization. These structures will underpin the future structure-based development of DOP agonists for an improved pain treatment with fewer adverse effects.

引用

页数：12

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