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.
Grace
Christy R R
CR
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
Perrin
Marilyn H
MH
DiGruccio
Michael R
MR
Miller
Charleen L
CL
Rivier
Jean E
JE
Vale
Wylie W
WW
Riek
Roland
R
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