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 AMY₃R, and San45 bound to AMY₃R 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 AMY₃R. Targeted lipid modification may provide a single intervention strategy for design of long-acting, nonselective, Amy-based DACRAs with potential anti-obesity effects.

胰淀素受体 (AMYR) 是降钙素受体 (CTR) 的异二聚体，也是三种受体活性修饰蛋白之一，是有希望的肥胖目标。 Amy 激活 AMYR 的一个标志是形成“旁路”二级结构基序（残基 S19-P25）。本研究探索了通过修饰 19-22 号残基来调节肽选择性的潜在可能性，从而产生选择性 AMYR 激动剂 San385 以及非选择性双胰淀素和降钙素受体激动剂 (DACRA)，其中 San45 就是一个例子。我们确定了与 San385 结合的 AMY ₃ R 以及与 AMY ₃ R 或 CTR 结合的 San45 的结构和动力学。 San45 通过其在位置 21 处的缀合脂质锚定在受体束的边缘，除了与 AMY ₃ R 结合的旁路模式外，还可以在与 CTR 结合时实现稳定的替代结合模式。为设计具有潜在抗肥胖作用的长效、非选择性、基于 Amy 的 DACRA 提供单一干预策略。