A structural basis for amylin receptor phenotype

被引：44

作者：

Cao, Jianjun ^{[1
,2
]}

Belousoff, Matthew J. ^{[1
,2
,5
]}

Liang, Yi-Lynn ^{[1
]}

Johnson, Rachel M. ^{[1
,2
]}

Josephs, Tracy M. ^{[1
,2
]}

Fletcher, Madeleine M. ^{[1
,6
]}

Christopoulos, Arthur ^{[1
,2
]}

Hay, Debbie L. ^{[3
]}

Danev, Radostin ^{[4
]}

Wootten, Denise ^{[1
,2
]}

Sexton, Patrick M. ^{[1
,2
]}

机构：

[1] Monash Univ, Monash Inst Pharmaceut Sci, Drug Discovery Biol Theme, Parkville, Vic 3052, Australia

[2] Monash Univ, ARC Ctr Cryo Electron Microscopy Membrane Prot, Monash Inst Pharmaceut Sci, Parkville, Vic 3052, Australia

[3] Univ Otago, Dept Pharmacol & Toxicol, Dunedin 9054, New Zealand

[4] Univ Tokyo, Grad Sch Med, Bunkyo Ku, N415,7-3-1 Hongo, Tokyo 1130033, Japan

[5] Confo Therapeut, B-9052 Ghent, Belgium

[6] GlaxoSmithKline, Abbotsford, Vic 3067, Australia

来源：

SCIENCE | 2022年 / 375卷 / 6587期

基金：

美国国家卫生研究院; 澳大利亚研究理事会; 英国医学研究理事会; 日本科学技术振兴机构;

关键词：

GENE-RELATED PEPTIDE; CRYO-EM STRUCTURE; CALCITONIN RECEPTOR; SALMON-CALCITONIN; DUAL AMYLIN; BODY-WEIGHT; DIFFERENTIALLY MODULATE; PROTEIN-INTERACTION; BINDING; PRAMLINTIDE;

D O I：

10.1126/science.abm9609

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：

Amylin receptors (AMYRs) are heterodimers of the calcitonin (CT) receptor (CTR) and one of three receptor activity-modifying proteins (RAMPs), AMY(1)R, AMY(2)R, and AMY(3)R. Selective AMYR agonists and dual AMYR/CTR agonists are being developed as obesity treatments; however, the molecular basis for peptide binding and selectivity is unknown. We determined the structure and dynamics of active AMYRs with amylin, AMY(1)R with salmon CT (sCT), AMY(2)R with sCT or human CT (hCT), and CTR with amylin, sCT, or hCT. The conformation of amylin-bound complexes was similar for all AMYRs, constrained by the RAMP, and an ordered midpeptide motif that we call the bypass motif. The CT-bound AMYR complexes were distinct, overlapping the CT-bound CTR complexes. Our findings indicate that activation of AMYRs by CT-based peptides is distinct from their activation by amylin-based peptides. This has important implications for the development of AMYR therapeutics.

引用

页码：1371 / +

页数：47

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