7TYX

Human Amylin2 Receptor in complex with Gs and rat amylin peptide

Summary for 7TYX

• Entry DOI: 10.2210/pdb7tyx/pdb
• EMDB information: 26197
• Descriptor: Receptor activity-modifying protein 2, CHOLESTEROL HEMISUCCINATE, amylin peptide, ... (10 entities in total)
• Functional Keywords: amylin receptor, gpcr, ramp2, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 7
• Total formula weight: 191141.24

Authors

Cao, J.,Belousoff, M.J.,Johnson, R.M.,Wootten, D.L.,Sexton, P.M. (deposition date: 2022-02-14, release date: 2022-03-30, Last modification date: 2024-10-16)

Primary citation

Cao, J.,Belousoff, M.J.,Liang, Y.L.,Johnson, R.M.,Josephs, T.M.,Fletcher, M.M.,Christopoulos, A.,Hay, D.L.,Danev, R.,Wootten, D.,Sexton, P.M.
A structural basis for amylin receptor phenotype.
Science, 375:eabm9609-eabm9609, 2022

PubMed Abstract: Amylin receptors (AMYRs) are heterodimers of the calcitonin (CT) receptor (CTR) and one of three receptor activity-modifying proteins (RAMPs), AMYR, AMYR, and AMYR. Selective AMYR agonists and dual AMYR/CTR agonists are being developed as obesity treatments; however, the molecular basis for peptide binding and selectivity is unknown. We determined the structure and dynamics of active AMYRs with amylin, AMYR with salmon CT (sCT), AMYR with sCT or human CT (hCT), and CTR with amylin, sCT, or hCT. The conformation of amylin-bound complexes was similar for all AMYRs, constrained by the RAMP, and an ordered midpeptide motif that we call the bypass motif. The CT-bound AMYR complexes were distinct, overlapping the CT-bound CTR complexes. Our findings indicate that activation of AMYRs by CT-based peptides is distinct from their activation by amylin-based peptides. This has important implications for the development of AMYR therapeutics.

PubMed: 35324283
DOI: 10.1126/science.abm9609

Experimental method

ELECTRON MICROSCOPY (2.55 Å)