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

Jason M Booe, Christopher S Walker, James Barwell, Gabriel Kuteyi, John Simms, Muhammad A Jamaluddin, Margaret L Warner, Roslyn M Bill, Paul W Harris, Margaret A Brimble, David R Poyner, Debbie L Hay, Augen A Pioszak

Research output: Contribution to journalArticle

51 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1040-52
Number of pages13
JournalMolecular Cell
Volume58
Issue number6
DOIs
Publication statusPublished - 18 Jun 2015
Externally publishedYes

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Receptor Activity-Modifying Proteins
Calcitonin Receptor-Like Protein
G-Protein-Coupled Receptors
Peptides
Adrenomedullin
Calcitonin Gene-Related Peptide
Receptor Activity-Modifying Protein 3
Binding Sites
Lymphatic System
Drug Delivery Systems
Cardiovascular System
Membrane Proteins
Pharmacology
Ligands

Keywords

  • Adrenomedullin
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • COS Cells
  • Calcitonin Gene-Related Peptide
  • Calcitonin Receptor-Like Protein
  • Cercopithecus aethiops
  • Crystallography, X-Ray
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Peptides
  • Protein Binding
  • Protein Multimerization
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Receptor Activity-Modifying Protein 1
  • Receptor Activity-Modifying Protein 2
  • Sequence Homology, Amino Acid
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

Cite this

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

In: Molecular Cell, Vol. 58, No. 6, 18.06.2015, p. 1040-52.

Research output: Contribution to journalArticle

Booe, JM, Walker, CS, Barwell, J, Kuteyi, G, Simms, J, Jamaluddin, MA, Warner, ML, Bill, RM, Harris, PW, Brimble, MA, Poyner, DR, Hay, DL & Pioszak, AA 2015, 'Structural Basis for Receptor Activity-Modifying Protein-Dependent Selective Peptide Recognition by a G Protein-Coupled Receptor' Molecular Cell, vol. 58, no. 6, pp. 1040-52. 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 ; Pioszak, Augen A. / Structural Basis for Receptor Activity-Modifying Protein-Dependent Selective Peptide Recognition by a G Protein-Coupled Receptor. In: Molecular Cell. 2015 ; Vol. 58, No. 6. pp. 1040-52.
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T1 - Structural Basis for Receptor Activity-Modifying Protein-Dependent Selective Peptide Recognition by a G Protein-Coupled Receptor

AU - Booe, Jason M

AU - Walker, Christopher S

AU - Barwell, James

AU - Kuteyi, Gabriel

AU - Simms, John

AU - Jamaluddin, Muhammad A

AU - Warner, Margaret L

AU - Bill, Roslyn M

AU - Harris, Paul W

AU - Brimble, Margaret A

AU - Poyner, David R

AU - Hay, Debbie L

AU - Pioszak, Augen A

N1 - Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2015/6/18

Y1 - 2015/6/18

N2 - 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.

AB - 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.

KW - Adrenomedullin

KW - Amino Acid Sequence

KW - Animals

KW - Binding Sites

KW - COS Cells

KW - Calcitonin Gene-Related Peptide

KW - Calcitonin Receptor-Like Protein

KW - Cercopithecus aethiops

KW - Crystallography, X-Ray

KW - Humans

KW - Models, Molecular

KW - Molecular Sequence Data

KW - Mutation

KW - Peptides

KW - Protein Binding

KW - Protein Multimerization

KW - Protein Structure, Secondary

KW - Protein Structure, Tertiary

KW - Receptor Activity-Modifying Protein 1

KW - Receptor Activity-Modifying Protein 2

KW - Sequence Homology, Amino Acid

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

KW - Research Support, U.S. Gov't, Non-P.H.S.

U2 - 10.1016/j.molcel.2015.04.018

DO - 10.1016/j.molcel.2015.04.018

M3 - Article

VL - 58

SP - 1040

EP - 1052

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 6

ER -