Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
Nat Chem Biol. 2024 Feb;20(2):162-169. doi: 10.1038/s41589-023-01393-4. Epub 2023 Aug 3.
Amylin receptors (AMYRs), heterodimers of the calcitonin receptor (CTR) and one of three receptor activity-modifying proteins, are promising obesity targets. A hallmark of AMYR activation by Amy is the formation of a 'bypass' secondary structural motif (residues S19-P25). This study explored potential tuning of peptide selectivity through modification to residues 19-22, resulting in a selective AMYR agonist, San385, as well as nonselective dual amylin and calcitonin receptor agonists (DACRAs), with San45 being an exemplar. We determined the structure and dynamics of San385-bound AMYR, and San45 bound to AMYR or CTR. San45, via its conjugated lipid at position 21, was anchored at the edge of the receptor bundle, enabling a stable, alternative binding mode when bound to the CTR, in addition to the bypass mode of binding to AMYR. Targeted lipid modification may provide a single intervention strategy for design of long-acting, nonselective, Amy-based DACRAs with potential anti-obesity effects.
胰岛淀粉样多肽受体（AMYRs）是降钙素受体（CTR）与三种受体活性修饰蛋白之一的异二聚体，是有前途的肥胖治疗靶点。AMYR 被胰岛淀粉样多肽激活的一个标志是形成“旁路”二级结构模体（残基 S19-P25）。本研究通过修饰残基 19-22 探索了对肽选择性进行潜在调整的可能性，从而产生了选择性 AMYR 激动剂 San385，以及非选择性双重胰岛淀粉样多肽和降钙素受体激动剂（DACRAs），San45 就是一个典型代表。我们确定了 San385 结合 AMYR 的结构和动力学，以及 San45 结合 AMYR 或 CTR 的结构和动力学。San45 通过其在位置 21 上的共轭脂质锚定在受体束的边缘，使其在结合到 CTR 时能够形成稳定的、替代的结合模式，除了结合 AMYR 的旁路模式之外。靶向脂质修饰可能为设计长效、非选择性、基于 Amy 的 DACRAs 提供一种单一的干预策略，具有潜在的抗肥胖作用。
