澳大利亚莫纳什大学Patrick M. Sexton和Denise Wootten研究团队合作取得取得最新进展。他们揭示胰淀素受体表型的结构基础，相关论文发表在2022年3月25日出版的《科学》杂志上。

研究人员确定了活性胰淀素受体 (AMYR)与胰淀素、AMY1R 与鲑鱼降钙素 (CT) (sCT)、AMY2R 与 sCT 或人类 CT (hCT) 以及CT受体 (CTR)与胰淀素、sCT 或 hCT 的结构和动力学。所有 AMYR 的胰淀素结合复合物的构象都相似，受受体活性修饰蛋白 (RAMP)和我们称之为旁路基序的有序中肽基序的约束。CT 结合的 AMYR 复合物是不同的，与 CT 结合的 CTR 复合物重叠。他们的研究结果表明，基于 CT 的肽对 AMYR 的激活不同于它们由基于胰淀素的肽的激活。这对 AMYR 疗法的发展具有重要意义。

据介绍，AMYR是CTR的异二聚体，是三种RAMP（AMY1R、AMY2R 和 AMY3R）之一。 正在开发选择性 AMYR 激动剂和双重 AMYR/CTR 激动剂作为肥胖治疗； 然而，肽结合和选择性的分子基础是未知的。

附：英文原文

Title: A structural basis for amylin receptor phenotype

Author: Jianjun Cao, Matthew J. Belousoff, Yi-Lynn Liang, Rachel M. Johnson, Tracy M. Josephs, Madeleine M. Fletcher, Arthur Christopoulos, Debbie L. Hay, Radostin Danev, Denise Wootten, Patrick M. Sexton

Issue&Volume: 2022-03-25

Abstract: Amylin receptors (AMYRs) are heterodimers of the calcitonin (CT) receptor (CTR) and one of three receptor activity–modifying proteins (RAMPs), AMY1R, AMY2R, and AMY3R. 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, AMY1R with salmon CT (sCT), AMY2R 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.

DOI: abm9609

Source: https://www.science.org/doi/10.1126/science.abm9609