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Structure paper

TitleA structural basis for amylin receptor phenotype.
Journal, issue, pagesScience, Vol. 375, Issue 6587, Page eabm9609, Year 2022
Publish dateMar 25, 2022
AuthorsJianjun 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 AbstractAmylin 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 linksScience / PubMed:35324283
MethodsEM (single particle)
Resolution2.2 - 3.3 Å
Structure data

EMDB-26178, PDB-7tyf:
Human Amylin1 Receptor in complex with Gs and rat amylin peptide
Method: EM (single particle) / Resolution: 2.2 Å

EMDB-26179, PDB-7tyh:
Human Amylin2 Receptor in complex with Gs and human calcitonin peptide
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-26180, PDB-7tyi:
Calcitonin Receptor in complex with Gs and rat amylin peptide, CT-like state
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-26184, PDB-7tyl:
Calcitonin Receptor in complex with Gs and rat amylin peptide, bypass motif
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-26188, PDB-7tyn:
Calcitonin Receptor in complex with Gs and salmon calcitonin peptide
Method: EM (single particle) / Resolution: 2.6 Å

EMDB-26190, PDB-7tyo:
Calcitonin receptor in complex with Gs and human calcitonin peptide
Method: EM (single particle) / Resolution: 2.7 Å

EMDB-26196, PDB-7tyw:
Human Amylin1 Receptor in complex with Gs and salmon calcitonin peptide
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-26197, PDB-7tyx:
Human Amylin2 Receptor in complex with Gs and rat amylin peptide
Method: EM (single particle) / Resolution: 2.55 Å

EMDB-26199, PDB-7tyy:
Human Amylin2 Receptor in complex with Gs and salmon calcitonin peptide
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-26208, PDB-7tzf:
Human Amylin3 Receptor in complex with Gs and rat amylin peptide
Method: EM (single particle) / Resolution: 2.4 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-PLM:
PALMITIC ACID

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-P42:
(2S)-2-{[(1R)-1-hydroxyhexadecyl]oxy}-3-{[(1R)-1-hydroxyoctadecyl]oxy}propyl 2-(trimethylammonio)ethyl phosphate / SPPC, phospholipid*YM

ChemComp-PTY:
PHOSPHATIDYLETHANOLAMINE / phospholipid*YM

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
  • lama glama (llama)
  • rattus norvegicus (Norway rat)
  • salmo salar (Atlantic salmon)
KeywordsMEMBRANE PROTEIN / Amylin receptor / GPCR / RAMP / RAMP2 / human calcitonin / calcitonin / CT-like / Amylin / bypass motif / calcitonin receptor / salmon calcitonin / RAMP1 / RAMP3 / rat amylin

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