2o8z

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Bound Structure of CRF1 Extracellular Domain Antagonist

Overview

Natural peptide agonists of corticotrophin-releasing factor (CRF), receptors bind to the receptor by a two-site mechanism as follows: the, carboxyl end of the ligand binds the N-terminal extracellular domain (ECD), of the receptor and the amino portion of the ligand binds the, extracellular face of the seven transmembrane region. Recently, peptide, antagonists homologous to the 12 C-terminal residues of CRF have been, derived, which bind the CRF(1) receptor through an interaction with the, ECD. Here we characterized the binding of a minimal 12-residue peptide, antagonist while bound to the isolated ECD of the CRF(1) receptor. We have, expressed and purified soluble and properly folded ECD independent from, the seven-transmembrane region as a thioredoxin fusion protein in, Escherichia coli. A model of the peptide antagonist, cyclic, corticotrophin-releasing factor residues 30-41 (cCRF(30-41)), was, calculated while bound to the recombinant ECD using transferred nuclear, Overhauser effect spectroscopy. Although the peptide is unstructured in, solution, it adopts an alpha-helical conformation when bound to the ECD., Residues of cCRF(30-41) comprising the binding interface with the ECD were, mapped using saturation transfer difference NMR. Two hydrophobic residues, (Met(38) and Ile(41)) as well as two amide groups (Asn(34) and the, C-terminal amide) on one face of the helix defined the binding epitope of, the antagonist. This epitope may be used as a starting point for, development of non-peptide antagonists targeting the ECD of this receptor.

About this Structure

2O8Z is a Protein complex structure of sequences from [1] with as ligand. Full crystallographic information is available from OCA.

Reference

NMR structural characterization of a minimal peptide antagonist bound to the extracellular domain of the corticotropin-releasing factor1 receptor., Mesleh MF, Shirley WA, Heise CE, Ling N, Maki RA, Laura RP, J Biol Chem. 2007 Mar 2;282(9):6338-46. Epub 2006 Dec 27. PMID:17192263

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