Structure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor

被引：285

作者：

Che, Tao ^{[1
]}

Majumdar, Susruta ^{[2
,3
]}

Zaidi, Saheem A. ^{[4
]}

Ondachi, Pauline ^{[5
]}

McCorvy, John D. ^{[1
]}

Wang, Sheng ^{[1
]}

Mosier, Philip D. ^{[6
,7
]}

Uprety, Rajendra ^{[2
,3
]}

Vardy, Eyal ^{[1
]}

Krumm, Brian E. ^{[1
]}

Han, Gye Won ^{[8
]}

Lee, Ming-Yue ^{[8
,9
,10
]}

Pardon, Els ^{[11
,12
]}

Steyaert, Jan ^{[11
,12
]}

Huang, Xi-Ping ^{[13
]}

Strachan, Ryan T. ^{[1
]}

Tribo, Alexandra R. ^{[1
]}

Pasternak, Gavril W. ^{[2
,3
]}

Carroll, F. Ivy ^{[5
]}

Stevens, Raymond C. ^{[4
,8
]}

Cherezov, Vadim ^{[8
]}

Katritch, Vsevolod ^{[4
,8
]}

Wacker, Daniel ^{[1
]}

Roth, Bryan L. ^{[1
,13
,14
]}

机构：

[1] Univ North Carolina Chapel Hill, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA

[2] Mem Sloan Kettering Canc Ctr, Mol Pharmacol Program, New York, NY 10065 USA

[3] Mem Sloan Kettering Canc Ctr, Dept Neurol, New York, NY 10065 USA

[4] Univ Southern Calif, Dept Biol Sci, Bridge Inst, Los Angeles, CA 90089 USA

[5] Res Triangle Inst, Ctr Organ & Med Chem, POB 12194, Res Triangle Pk, NC 27709 USA

[6] Virginia Commonweath Univ, Dept Med Chem, Richmond, VA 23298 USA

[7] Virginia Commonweath Univ, Inst Struct Biol Drug Discovery & Dev, Richmond, VA 23298 USA

[8] Univ Southern Calif, Dept Chem, Bridge Inst, Los Angeles, CA 90089 USA

[9] Arizona State Univ, Sch Mol Sci, Biodesign Ctr Appl Struct Discovery, Biodesign Inst, Tempe, AZ 85287 USA

[10] Nanjing Audit Univ, Inst Nat Resources & Environm Audits, Nanjing, Jiangsu, Peoples R China

[11] Vrije Univ Brussel, Struct Biol Brussels, B-1050 Brussels, Belgium

[12] VIB, VIB VUB Ctr Struct Biol, B-1050 Brussels, Belgium

[13] Univ North Carolina Chapel Hill, Sch Med, NIMH PDSP, Chapel Hill, NC 27599 USA

[14] Univ North Carolina Chapel Hill, Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA

来源：

CELL | 2018年 / 172卷 / 1-2期

关键词：

PROTEIN-COUPLED RECEPTORS; STRUCTURE-BASED DISCOVERY; CRYSTAL-STRUCTURE; FORCE-FIELD; POTENT ANTINOCICEPTION; FUNCTIONAL SELECTIVITY; AGONIST; MU; COMPLEX; BINDING;

D O I：

10.1016/j.cell.2017.12.011

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The kappa-opioid receptor (KOP) mediates the actions of opioids with hallucinogenic, dysphoric, and analgesic activities. The design of KOP analgesics devoid of hallucinatory and dysphoric effects has been hindered by an incomplete structural and mechanistic understanding of KOP agonist actions. Here, we provide a crystal structure of human KOP in complex with the potent epoxymorphinan opioid agonist MP1104 and an active-state-stabilizing nanobody. Comparisons between inactive-and active-state opioid receptor structures reveal substantial conformational changes in the binding pocket and intracellular and extracellular regions. Extensive structural analysis and experimental validation illuminate key residues that propagate larger-scale structural rearrangements and transducer binding that, collectively, elucidate the structural determinants of KOP pharmacology, function, and biased signaling. These molecular insights promise to accelerate the structure-guided design of safer and more effective k-opioid receptor therapeutics.

引用

页码：55 / +

页数：28

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