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-Structure paper
Title | A structural basis for amylin receptor phenotype. |
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Journal, issue, pages | Science, Vol. 375, Issue 6587, Page eabm9609, Year 2022 |
Publish date | Mar 25, 2022 |
Authors | Jianjun Cao / Matthew J Belousoff / Yi-Lynn Liang / Rachel M Johnson / Tracy M Josephs / Madeleine M Fletcher / Arthur Christopoulos / Debbie L Hay / Radostin Danev / Denise Wootten / Patrick M Sexton / |
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 ...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. |
External links | Science / PubMed:35324283 |
Methods | EM (single particle) |
Resolution | 2.2 - 3.3 Å |
Structure data | EMDB-26178, PDB-7tyf: EMDB-26179, PDB-7tyh: EMDB-26180, PDB-7tyi: EMDB-26184, PDB-7tyl: EMDB-26188, PDB-7tyn: EMDB-26190, PDB-7tyo: EMDB-26196, PDB-7tyw: EMDB-26197, PDB-7tyx: EMDB-26199, PDB-7tyy: EMDB-26208, PDB-7tzf: |
Chemicals | ChemComp-NAG: ChemComp-PLM: ChemComp-Y01: ChemComp-P42: ChemComp-PTY: ChemComp-HOH: |
Source |
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Keywords | MEMBRANE PROTEIN / Amylin receptor / GPCR / RAMP / RAMP2 / human calcitonin / calcitonin / CT-like / Amylin / bypass motif / calcitonin receptor / salmon calcitonin / RAMP1 / RAMP3 / rat amylin |