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

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. Lastly, 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.
Authors:
 [1] ;  [2] ;  [3] ;  [4] ;  [5] ;  [2] ;  [1] ;  [5] ;  [2] ;  [2] ;  [5] ;  [2] ;  [1]
  1. Univ. of Oklahoma Health Sciences Center, Oklahoma City, OK (United States)
  2. Univ. of Auckland, Auckland (New Zealand)
  3. Aston Univ., Birmingham (United Kingdom); Adaptimmune Ltd., Abingdon (United Kingdom)
  4. Aston Univ., Birmingham (United Kingdom); Univ. of Oxford, Oxford (United Kingdom)
  5. Aston Univ., Birmingham (United Kingdom)
Publication Date:
OSTI Identifier:
1295950
Grant/Contract Number:
AC02-06CH11357
Type:
Published Article
Journal Name:
Molecular Cell
Additional Journal Information:
Journal Volume: 58; Journal Issue: 6; Journal ID: ISSN 1097-2765
Publisher:
Elsevier - Cell Press
Research Org:
Univ. of Oklahoma Health Sciences Center, Oklahoma City, OK (United States)
Sponsoring Org:
USDOE Office of Science (SC)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES