NMR structure and peptide hormone binding site of the first extracellular domain of a type B1 G protein-coupled receptor.
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.
Structural Biology Laboratory, and The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. perrin@salk.edu
Christy R R
CR
Grace
Marilyn H
MH
Perrin
Michael R
MR
DiGruccio
Charleen L
CL
Miller
Jean E
JE
Rivier
Wylie W
WW
Vale
Roland
R
Riek
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008969:Molecular Sequence Data; D036361:Peptide Hormones / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000378:metabolism
D036361:Peptide Hormones; D043562:Receptors, G-Protein-Coupled