4RWG

Crystal structure of the CLR:RAMP1 extracellular domain heterodimer with bound high affinity CGRP analog

Summary for 4RWG

• Entry DOI: 10.2210/pdb4rwg/pdb
• Related: 4RWF
• Related PRD ID: PRD_900001
• Descriptor: Maltose-binding periplasmic protein, Receptor activity-modifying protein 1, Calcitonin gene-related peptide type 1 receptor fusion protein, CGRP analog, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: cell surface receptor, membrane protein-hormone complex, membrane protein/hormone
• Biological source: Escherichia coli; More
• Total number of polymer chains: 6
• Total formula weight: 203547.95

Authors

Booe, J.,Pioszak, A. (deposition date: 2014-12-03, release date: 2015-05-20, Last modification date: 2024-11-27)

Primary citation

Booe, J.M.,Walker, C.S.,Barwell, J.,Kuteyi, G.,Simms, J.,Jamaluddin, M.A.,Warner, M.L.,Bill, R.M.,Harris, P.W.,Brimble, M.A.,Poyner, D.R.,Hay, D.L.,Pioszak, A.A.
Structural Basis for Receptor Activity-Modifying Protein-Dependent Selective Peptide Recognition by a G Protein-Coupled Receptor.
Mol.Cell, 58:1-13, 2015

PubMed 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.

PubMed: 25982113
DOI: 10.1016/j.molcel.2015.04.018

Experimental method

X-RAY DIFFRACTION (2.44 Å)