NMR Structure and Peptide Hormone Binding Site of the First Extracellular Domain of a Type B1 G Protein-coupled Receptor

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2004 Aug 25

PMID 15326300

Citations 83

Authors

Christy R R Grace

Marilyn H Perrin

Michael R DiGruccio

Charleen L Miller

Jean E Rivier

Wylie W Vale

Roland Riek

Affiliations

Soon will be listed here.

Abstract

The corticotropin-releasing factor (CRF) ligand family has diverse effects on the CNS, including the modulation of the stress response. The ligands' effects are mediated by binding to CRF G protein-coupled receptors. We have determined the 3D NMR structure of the N-terminal extracellular domain (ECD1) of the mouse CRF receptor 2beta, which is the major ligand recognition domain, and identified its ligand binding site by chemical-shift perturbation experiments. The fold is identified as a short consensus repeat (SCR), a common protein interaction module. Mutagenesis reveals the integrity of the hormone-binding site in the full-length receptor. This study proposes that the ECD1 captures the C-terminal segment of the ligand, whose N terminus then penetrates into the transmembrane region of the receptor to initiate signaling. Key residues of SCR in the ECD1 are conserved in the G protein-coupled receptor subfamily, suggesting the SCR fold in all of the ECD1s of this subfamily.

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