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

doi:10.1126/sciadv.aax9115

	Elucidating the active delta-opioid receptor crystal structure with peptide and small-molecule agonists
	Claff, Tobias 1,2; Yu, Jing1,3,4,5 ; Blais, Veronique 6; Patel, Nilkanth 7,8; Martin, Charlotte 9; Wu, Lijie1 ; 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-Jie1,3 ; Mueller, Christa E.2; Stevens, Raymond C.1,7,8
	2019-11
发表期刊	SCIENCE ADVANCES
ISSN	2375-2548
卷号	5 期号:11
发表状态	已发表
DOI	10.1126/sciadv.aax9115
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.
URL	查看原文
收录类别	SCI ; SCIE
语种	英语
资助项目	Canadian Institute of Health Research (CIHR)[MOP-123399] ; Canadian Institute of Health Research (CIHR)[MOP-136871]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:000499736100077
出版者	AMER ASSOC ADVANCEMENT SCIENCE
WOS关键词	MEMBRANE-PROTEINS ; POTENT ; ANALGESIA ; LACKING ; MODELS ; TARGET ; BRAIN ; STATE
原始文献类型	Article
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/104523
专题	iHuman研究所_科学装置(X)_膜蛋白同步辐射线站 iHuman研究所_特聘教授组_Raymond Stevens组 iHuman研究所_PI研究组_刘志杰组生命科学与技术学院_博士生
通讯作者	Mueller, Christa E.; Stevens, Raymond C.
作者单位	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
第一作者单位	iHuman研究所
通讯作者单位	iHuman研究所
第一作者的第一单位	iHuman研究所
推荐引用方式 GB/T 7714	Claff, Tobias,Yu, Jing,Blais, Veronique,et al. Elucidating the active delta-opioid receptor crystal structure with peptide and small-molecule agonists[J]. SCIENCE ADVANCES,2019,5(11).
APA	Claff, Tobias.,Yu, Jing.,Blais, Veronique.,Patel, Nilkanth.,Martin, Charlotte.,...&Stevens, Raymond C..(2019).Elucidating the active delta-opioid receptor crystal structure with peptide and small-molecule agonists.SCIENCE ADVANCES,5(11).
MLA	Claff, Tobias,et al."Elucidating the active delta-opioid receptor crystal structure with peptide and small-molecule agonists".SCIENCE ADVANCES 5.11(2019).