Structural basis for receptor activity-modifying protein-dependent selective peptide recognition by a G protein-coupled receptor

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Abstract

Association of receptor activity-modifying proteins (RAMP1-3) with the G protein-coupled receptor (GPCR) calcitonin receptor-like receptor (CLR) enables selective recognition of the peptides calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) that have diverse functions in the cardiovascular and lymphatic systems. How peptides selectively bind GPCR:RAMP complexes is unknown. We report crystal structures of CGRP analog-bound CLR:RAMP1 and AM-bound CLR:RAMP2 extracellular domain heterodimers at 2.5 and 1.8 Å resolutions, respectively. The peptides similarly occupy a shared binding site on CLR with conformations characterized by a β-turn structure near their C termini rather than the α-helical structure common to peptides that bind related GPCRs. The RAMPs augment the binding site with distinct contacts to the variable C-terminal peptide residues and elicit subtly different CLR conformations. The structures and accompanying pharmacology data reveal how a class of accessory membrane proteins modulate ligand binding of a GPCR and may inform drug development targeting CLR:RAMP complexes.

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Original languageEnglish
Pages (from-to)1040-1052
Number of pages13
JournalMolecular Cell
Volume58
Issue number6
Early online date14 May 2015
DOIs
Publication statusPublished - 18 Jun 2015

Bibliographic note

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) Open Access funded by Wellcome Trust Funding: NIH grant R01GM104251 (A.A.P.), Wellcome Trust grant 091496 (D.R.P.), and grants from the Marsden Fund and Health Research Council of New Zealand (D.L.H.). Use of the Leica microscope for crystal imaging was supported by an Institutional Developmental Award from the National Institute of General Medical Sciences of the NIH under grant number P20GM103640. Use of the Advanced Photon Source, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the U.S. DOE under Contract No. DE-AC02-06CH11357. Use of the LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor (Grant 085P1000817).

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