RGD Reference Report - A structural basis for amylin receptor phenotype. - Rat Genome Database

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A structural basis for amylin receptor phenotype.

Authors: Cao, Jianjun  Belousoff, Matthew J  Liang, Yi-Lynn  Johnson, Rachel M  Josephs, Tracy M  Fletcher, Madeleine M  Christopoulos, Arthur  Hay, Debbie L  Danev, Radostin  Wootten, Denise  Sexton, Patrick M 
Citation: Cao J, etal., Science. 2022 Mar 25;375(6587):eabm9609. doi: 10.1126/science.abm9609. Epub 2022 Mar 25.
RGD ID: 408345209
Pubmed: PMID:35324283   (View Abstract at PubMed)
DOI: DOI:10.1126/science.abm9609   (Journal Full-text)

Amylin receptors (AMYRs) are heterodimers of the calcitonin (CT) receptor (CTR) and one of three receptor activity-modifying proteins (RAMPs), AMY1R, AMY2R, and AMY3R. 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, AMY1R with salmon CT (sCT), AMY2R 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.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
IappRatamylin receptor signaling pathway involved_inIDA PMID:35324283UniProt 

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
IappRathormone activity enablesIDA PMID:35324283UniProt 
IappRatreceptor ligand activity enablesIDA PMID:35324283UniProt 

Objects Annotated

Genes (Rattus norvegicus)
Iapp  (islet amyloid polypeptide)


Additional Information