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:
- 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 Name: Molecular Cell Journal Volume: 58 Journal Issue: 6; Journal ID: ISSN 1097-2765
- Publisher:
- Elsevier
- 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. https://doi.org/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. Mon .
"Structural Basis for Receptor Activity-Modifying Protein-Dependent Selective Peptide Recognition by a G Protein-Coupled Receptor". United States. https://doi.org/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 = {Mon Jun 01 00:00:00 EDT 2015},
month = {Mon Jun 01 00:00:00 EDT 2015}
}
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https://doi.org/10.1016/j.molcel.2015.04.018
https://doi.org/10.1016/j.molcel.2015.04.018
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Works referencing / citing this record:
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