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. 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.affiliation: Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Booe
authors.affiliation: School of Biological Sciences and Maurice Wilkins Centre, University of Auckland, Auckland 1142, New Zealand.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Walker
authors.affiliation: School of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK.
authors.forename: James
authors.initials: J
authors.lastname: Barwell
authors.affiliation: School of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Kuteyi
authors.affiliation: School of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK.
authors.forename: John
authors.initials: J
authors.lastname: Simms
authors.affiliation: School of Biological Sciences and Maurice Wilkins Centre, University of Auckland, Auckland 1142, New Zealand.
authors.forename: Muhammad A
authors.initials: MA
authors.lastname: Jamaluddin
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Warner
authors.affiliation: School of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK.
authors.forename: Roslyn M
authors.initials: RM
authors.lastname: Bill
authors.affiliation: School of Chemical Sciences and Maurice Wilkins Centre, University of Auckland, Auckland 1142, New Zealand.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Harris
authors.affiliation: School of Chemical Sciences and Maurice Wilkins Centre, University of Auckland, Auckland 1142, New Zealand.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Brimble
authors.affiliation: School of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Poyner
authors.affiliation: School of Biological Sciences and Maurice Wilkins Centre, University of Auckland, Auckland 1142, New Zealand.
authors.forename: Debbie L
authors.initials: DL
authors.lastname: Hay
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. Electronic address: augen-pioszak@ouhsc.edu.
authors.forename: Augen A
authors.initials: AA
authors.lastname: Pioszak
mesh_terms: D053607:Adrenomedullin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D019556:COS Cells; D015740:Calcitonin Gene-Related Peptide / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D058286:Calcitonin Receptor-Like Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D058262:Receptor Activity-Modifying Protein 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D058263:Receptor Activity-Modifying Protein 2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D058286:Calcitonin Receptor-Like Protein; D010455:Peptides; C545502:RAMP1 protein, human; C545503:RAMP2 protein, human; D058262:Receptor Activity-Modifying Protein 1; D058263:Receptor Activity-Modifying Protein 2; D053607:Adrenomedullin; D015740:Calcitonin Gene-Related Peptide