9AUC

Human Amylin1 Receptor in Complex with Gs and human Calcitonin Gene-Related Peptide

Summary for 9AUC

• Entry DOI: 10.2210/pdb9auc/pdb
• EMDB information: 43877
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, CHOLESTEROL HEMISUCCINATE, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (11 entities in total)
• Functional Keywords: amylin receptor, gpcr, ramp3, calcitonin gene-related peptide, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 7
• Total formula weight: 189470.23

Authors

Cao, J.,Belousoff, M.J.,Wootten, D.L.,Sexton, P.M. (deposition date: 2024-02-28, release date: 2024-04-24, Last modification date: 2025-06-04)

Primary citation

Cao, J.,Belousoff, M.J.,Danev, R.,Christopoulos, A.,Wootten, D.,Sexton, P.M.
Cryo-EM Structure of the Human Amylin 1 Receptor in Complex with CGRP and Gs Protein.
Biochemistry, 63:1089-1096, 2024

PubMed Abstract: Inhibition of calcitonin gene-related peptide (CGRP) or its cognate CGRP receptor (CGRPR) has arisen as a major breakthrough in the treatment of migraine. However, a second CGRP-responsive receptor exists, the amylin (Amy) 1 receptor (AMYR), yet its involvement in the pathology of migraine is poorly understood. AMYR and CGRPR are heterodimers consisting of receptor activity-modifying protein 1 (RAMP1) with the calcitonin receptor (CTR) and the calcitonin receptor-like receptor (CLR), respectively. Here, we present the structure of AMYR in complex with CGRP and Gs protein and compare it with the reported structures of the AMYR complex with rat amylin (rAmy) and the CGRPR in complex with CGRP. Despite similar protein backbones observed within the receptors and the N- and C-termini of the two peptides bound to the AMYR complexes, they have distinct organization in the peptide midregions (the bypass motif) that is correlated with differences in the dynamics of the respective receptor extracellular domains. Moreover, divergent conformations of extracellular loop (ECL) 3, intracellular loop (ICL) 2, and ICL3 within the CTR and CLR protomers are evident when comparing the CGRP bound to the CGRPR and AMYR, which influences the binding mode of CGRP. However, the conserved interactions made by the C-terminus of CGRP to the CGRPR and AMYR are likely to account for cross-reactivity of nonpeptide CGRPR antagonists observed at AMYR, which also extends to other clinically used CGRPR blockers, including antibodies.

PubMed: 38603770
DOI: 10.1021/acs.biochem.4c00114

Experimental method

ELECTRON MICROSCOPY (2.4 Å)