Structural insight into selectivity of amylin and calcitonin receptor agonists

Jianjun Cao, Matthew J. Belousoff, Elliot Gerrard, Radostin Danev, Madeleine M. Fletcher, Emma Dal Maso, Herman Schreuder, Katrin Lorenz, Andreas Evers, Garima Tiwari, Melissa Besenius, Ziyu Li, Rachel M. Johnson, Denise Wootten, Patrick M. Sexton

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Abstract

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. [Figure not available: see fulltext.].

Original languageEnglish
Pages (from-to)162-169
Number of pages8
JournalNature Chemical Biology
Volume20
Issue number2
DOIs
Publication statusPublished - Feb 2024

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