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

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. 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:
Research Org.:
Univ. of Oklahoma Health Sciences Center, Oklahoma City, OK (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1295950
Alternate Identifier(s):
OSTI ID: 1344487
Grant/Contract Number:  
AC02-06CH11357
Resource 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
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Booe, Jason M., Walker, Christopher S., Barwell, James, Kuteyi, Gabriel, Simms, John, Jamaluddin, Muhammad A., Warner, Margaret L., Bill, Roslyn M., Harris, Paul W., Brimble, Margaret A., Poyner, David R., Hay, Debbie L., and Pioszak, Augen A. Structural basis for receptor activity-modifying protein-dependent selective peptide recognition by a G protein-coupled receptor. United States: N. p., 2015. Web. doi:10.1016/j.molcel.2015.04.018.
Booe, Jason M., Walker, Christopher S., Barwell, James, Kuteyi, Gabriel, Simms, John, Jamaluddin, Muhammad A., Warner, Margaret L., Bill, Roslyn M., Harris, Paul W., Brimble, Margaret A., Poyner, David R., Hay, Debbie L., & Pioszak, Augen A. Structural basis for receptor activity-modifying protein-dependent selective peptide recognition by a G protein-coupled receptor. United States. doi:10.1016/j.molcel.2015.04.018.
Booe, Jason M., Walker, Christopher S., Barwell, James, Kuteyi, Gabriel, Simms, John, Jamaluddin, Muhammad A., Warner, Margaret L., Bill, Roslyn M., Harris, Paul W., Brimble, Margaret A., Poyner, David R., Hay, Debbie L., and Pioszak, Augen A. Thu . "Structural basis for receptor activity-modifying protein-dependent selective peptide recognition by a G protein-coupled receptor". United States. doi:10.1016/j.molcel.2015.04.018.
@article{osti_1295950,
title = {Structural basis for receptor activity-modifying protein-dependent selective peptide recognition by a G protein-coupled receptor},
author = {Booe, Jason M. and Walker, Christopher S. and Barwell, James and Kuteyi, Gabriel and Simms, John and Jamaluddin, Muhammad A. and Warner, Margaret L. and Bill, Roslyn M. and Harris, Paul W. and Brimble, Margaret A. and Poyner, David R. and Hay, Debbie L. and Pioszak, Augen A.},
abstractNote = {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.},
doi = {10.1016/j.molcel.2015.04.018},
journal = {Molecular Cell},
number = 6,
volume = 58,
place = {United States},
year = {2015},
month = {5}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: 10.1016/j.molcel.2015.04.018

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Cited by: 29 works
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