8F2B

Amylin 3 Receptor in complex with Gs and Pramlintide analogue peptide San45

Summary for 8F2B

• Entry DOI: 10.2210/pdb8f2b/pdb
• EMDB information: 28812
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, PALMITIC ACID, (2S)-2-{[(1R)-1-hydroxyhexadecyl]oxy}-3-{[(1R)-1-hydroxyoctadecyl]oxy}propyl 2-(trimethylammonio)ethyl phosphate, ... (13 entities in total)
• Functional Keywords: gpcr, amylin receptor, dual amylin and calcitonin receptor agonists, signaling protein-immune system complex, signaling protein/immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 7
• Total formula weight: 191394.26

Authors

Cao, J.,Sexton, P.M.,Wootten, D.L.,Belousoff, M.J. (deposition date: 2022-11-07, release date: 2023-08-02, Last modification date: 2024-10-23)

Primary citation

Cao, J.,Belousoff, M.J.,Gerrard, E.,Danev, R.,Fletcher, M.M.,Dal Maso, E.,Schreuder, H.,Lorenz, K.,Evers, A.,Tiwari, G.,Besenius, M.,Li, Z.,Johnson, R.M.,Wootten, D.,Sexton, P.M.
Structural insight into selectivity of amylin and calcitonin receptor agonists.
Nat.Chem.Biol., 20:162-169, 2024

PubMed 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 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.

PubMed: 37537379
DOI: 10.1038/s41589-023-01393-4

Experimental method

ELECTRON MICROSCOPY (2 Å)