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Structure paper

TitleStructural insight into selectivity of amylin and calcitonin receptor agonists.
Journal, issue, pagesNat Chem Biol, Vol. 20, Issue 2, Page 162-169, Year 2024
Publish dateAug 3, 2023
AuthorsJianjun Cao / Matthew J Belousoff / Elliot Gerrard / Radostin Danev / Madeleine M Fletcher / Emma Dal Maso / Herman Schreuder / Katrin Lorenz / Andreas Evers / Garima Tiwari / Melissa Besenius / Ziyu Li / Rachel M Johnson / Denise Wootten / Patrick M Sexton /
PubMed AbstractAmylin 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 ...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.
External linksNat Chem Biol / PubMed:37537379
MethodsEM (single particle)
Resolution1.9 - 2.2 Å
Structure data

EMDB-28758, PDB-8f0j:
Calcitonin Receptor in complex with Gs and Pramlintide analogue peptide San45
Method: EM (single particle) / Resolution: 2.0 Å

EMDB-28759, PDB-8f0k:
Human Amylin3 Receptor in complex with Gs and Pramlintide analogue peptide San385
Method: EM (single particle) / Resolution: 1.9 Å

EMDB-28810, PDB-8f2a:
Human Amylin3 Receptor in complex with Gs and Pramlintide analogue peptide San385 (Cluster 5 conformation)
Method: EM (single particle) / Resolution: 2.2 Å

EMDB-28812, PDB-8f2b:
Amylin 3 Receptor in complex with Gs and Pramlintide analogue peptide San45
Method: EM (single particle) / Resolution: 2.0 Å

Chemicals

ChemComp-D6M:
N-hexadecanoyl-L-glutamic acid

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

ChemComp-PTY:
PHOSPHATIDYLETHANOLAMINE / phospholipid*YM

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-HOH:
WATER

Source
  • homo sapiens (human)
  • lama glama (llama)
KeywordsSIGNALING PROTEIN/IMMUNE SYSTEM / GPCR / calcitonin receptor / dual amylin and calcitonin receptor agonists / SIGNALING PROTEIN-IMMUNE SYSTEM complex / amylin receptor / receptor activity-modifying protein

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