Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Victoria, Australia.
ARC Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Victoria, Australia.
Science. 2022 Mar 25;375(6587):eabm9609. doi: 10.1126/science.abm9609.
Amylin receptors (AMYRs) are heterodimers of the calcitonin (CT) receptor (CTR) and one of three receptor activity-modifying proteins (RAMPs), AMYR, AMYR, and AMYR. 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, AMYR with salmon CT (sCT), AMYR 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.
胰岛淀粉样多肽受体（AMYRs）是降钙素（CT）受体（CTR）和三种受体活性修饰蛋白（RAMPs）之一的异二聚体，分别为 AMYR、AMYR 和 AMYR。选择性 AMYR 激动剂和双 AMYR/CTR 激动剂正在被开发为肥胖症治疗药物；然而，肽结合和选择性的分子基础尚不清楚。我们确定了与胰岛淀粉样多肽结合的活性 AMYRs、与鲑鱼 CT（sCT）结合的 AMYR、与 sCT 或人 CT（hCT）结合的 AMYR 以及与胰岛淀粉样多肽、sCT 或 hCT 结合的 CTR 的结构和动力学。结合 RAMP 和我们称之为旁路基序的有序中肽基序，所有 AMYRs 结合的胰岛淀粉样多肽复合物的构象都相似。结合 CT 的 AMYR 复合物是独特的，与结合 CT 的 CTR 复合物重叠。我们的研究结果表明，基于 CT 的肽激活 AMYRs 的方式与基于胰岛淀粉样多肽的肽激活 AMYRs 的方式不同。这对 AMYR 治疗药物的开发具有重要意义。
