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Mol Cell. 2015 Jun 18;58(6):1040-52. doi: 10.1016/j.molcel.2015.04.018. Epub 2015 May 14.

Structural Basis for Receptor Activity-Modifying Protein-Dependent Selective Peptide Recognition by a G Protein-Coupled Receptor.

Author information

1
Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
2
School of Biological Sciences and Maurice Wilkins Centre, University of Auckland, Auckland 1142, New Zealand.
3
School of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK.
4
School of Chemical Sciences and Maurice Wilkins Centre, University of Auckland, Auckland 1142, New Zealand.
5
Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. Electronic address: augen-pioszak@ouhsc.edu.

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.

PMID:
25982113
PMCID:
PMC4504005
DOI:
10.1016/j.molcel.2015.04.018
[Indexed for MEDLINE]
Free PMC Article

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