Structural insight into selectivity of amylin and calcitonin receptor agonists

  • Nat Chem Biol. 2024 Feb;20(2):162-169. doi: 10.1038/s41589-023-01393-4.
Jianjun Cao  1  2 ,  Matthew J Belousoff  1  2 ,  Elliot Gerrard  1  2 ,  Radostin Danev  3 ,  Madeleine M Fletcher  1  4 ,  Emma Dal Maso  1  2 ,  Herman Schreuder  5 ,  Katrin Lorenz  5 ,  Andreas Evers  5  6 ,  Garima Tiwari  5  7 ,  Melissa Besenius  5 ,  Ziyu Li  5 ,  Rachel M Johnson  1  2  8 ,  Denise Wootten  9  10 ,  Patrick M Sexton  11  12
Affiliations
  • 1. Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
  • 2. ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
  • 3. Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
  • 4. GlaxoSmithKline, Abbotsford, Victoria, Australia.
  • 5. Sanofi-Aventis Deutschland GmbH, R&D, Industriepark Hoechst, Frankfurt am Main, Germany.
  • 6. Merck Healthcare KGaA, Darmstadt, Germany.
  • 7. Janssen Vaccines and Prevention B.V., Leiden, the Netherlands.
  • 8. OMass Therapeutics, Oxford, UK.
  • 9. Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. [email protected].
  • 10. ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. [email protected].
  • 11. Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. [email protected].
  • 12. ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. [email protected].
PMID: 37537379 DOI: 10.1038/s41589-023-01393-4
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.

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