2L27

NMR Structure of the ECD1 of CRF-R1 in complex with a peptide agonist

Summary for 2L27

• Entry DOI: 10.2210/pdb2l27/pdb
• Related: 2JNC 2JND
• Descriptor: Corticotropin-releasing factor receptor 1, peptide agonist (2 entities in total)
• Functional Keywords: crf, ecd1, agonist, family b1, alpha helical crf, membrane protein, peptide binding protein
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane; Multi-pass membrane protein: P34998
• Total number of polymer chains: 2
• Total formula weight: 13560.15

Authors

Grace, C.R.R.,Perrin, M.H.,Gulyas, J.R.R.,Rivier, J.E.,Vale, W.W.,Riek, R.R. (deposition date: 2010-08-12, release date: 2010-09-01, Last modification date: 2024-11-06)

Primary citation

Grace, C.R.,Perrin, M.H.,Gulyas, J.,Rivier, J.E.,Vale, W.W.,Riek, R.
NMR structure of the first extracellular domain of corticotropin-releasing factor receptor 1 (ECD1-CRF-R1) complexed with a high affinity agonist.
J.Biol.Chem., 285:38580-38589, 2010

PubMed Abstract: The corticotropin-releasing factor (CRF) peptide hormone family members coordinate endocrine, behavioral, autonomic, and metabolic responses to stress and play important roles within the cardiovascular, gastrointestinal, and central nervous systems, among others. The actions of the peptides are mediated by activation of two G-protein-coupled receptors of the B1 family, CRF receptors 1 and 2 (CRF-R1 and CRF-R2α,β). The recently reported three-dimensional structures of the first extracellular domain (ECD1) of both CRF-R1 and CRF-R2β (Pioszak, A. A., Parker, N. R., Suino-Powell, K., and Xu, H. E. (2008) J. Biol. Chem. 283, 32900-32912; Grace, C. R., Perrin, M. H., Gulyas, J., Digruccio, M. R., Cantle, J. P., Rivier, J. E., Vale, W. W., and Riek, R. (2007) Proc. Natl. Acad. Sci. U.S.A. 104, 4858-4863) complexed with peptide antagonists provided a starting point in understanding the binding between CRF ligands and receptors at a molecular level. We now report the three-dimensional NMR structure of the ECD1 of human CRF-R1 complexed with a high affinity agonist, α-helical cyclic CRF. In the structure of the complex, the C-terminal residues (23-41) of α-helical cyclic CRF bind to the ECD1 of CRF-R1 in a helical conformation mainly along the hydrophobic face of the peptide in a manner similar to that of the antagonists in their corresponding ECD1 complex structures. Unique to this study is the observation that complex formation between an agonist and the ECD1-CRF-R1 promotes the helical conformation of the N terminus of the former, important for receptor activation (Gulyas, J., Rivier, C., Perrin, M., Koerber, S. C., Sutton, S., Corrigan, A., Lahrichi, S. L., Craig, A. G., Vale, W., and Rivier, J. (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 10575-10579).

PubMed: 20843795
DOI: 10.1074/jbc.M110.121897

Experimental method

SOLUTION NMR