Structural insights into RAMP modification of secretin family G protein-coupled receptors: Implications for drug development

Julia Archbold, Jack Flanagan, Harriet Watkins, Joseph Gingell, Debbie Hay

Research output: Contribution to journalArticleResearchpeer-review

61 Citations (Scopus)

Abstract

Secretin family G protein-coupled receptors (GPCRs) are important therapeutic targets for migraine, diabetes, bone disorders, inflammatory disorders and cardiovascular disease. They possess a large N-terminal extracellular domain (ECD) known to be the primary ligand-binding determinant. Structural determination of several secretin family GPCR ECDs in complex with peptide ligands has been achieved recently, providing insight into the molecular determinants of hormone binding. Some secretin family GPCRs associate with receptor activity-modifying proteins (RAMPs), resulting in changes to receptor pharmacology. Recently, the first crystal structure of a RAMP ECD in complex with a secretin family GPCR was solved, revealing the elegant mechanism governing receptor selectivity of small molecule antagonists of the calcitonin gene-related peptide (CGRP) receptor. Here we review the structural basis of ligand binding to secretin family GPCRs, concentrating on recent progress made on the structural basis of RAMP-modified GPCR pharmacology and its implications for rational drug design.
Original languageEnglish
Pages (from-to)591 - 600
Number of pages10
JournalTrends in Pharmacological Sciences
Volume32
Issue number10
DOIs
Publication statusPublished - 2011

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