Work

A model of the thyrotropin-releasing hormone (TRH) receptor binding pocket. Evidence for a second direct interaction between transmembrane helix 3 and TRH.

Year: 1994

Type: article

Abstract: The receptor for thyrotropin-releasing hormone (TRH) is a member of the seven-transmembrane-spanning, GTP-binding protein-coupled receptor family. We showed that tyrosine at position 106 in transmembrane helix 3 of the TRH receptor directly binds the ring carbonyl of the pyroglutamyl moiety of TRH (Perlman, J. H., Thaw, C. N., Laakkonen L., Bowers, C. Y., Osman, R., and Gershengorn, M. C. (1994) J. Biol. Chem. 269, 1610-1613). We now show that asparagine at position 110 of transmembrane helix 3 directly interacts with the ring N-H of the TRH pyroglutamyl moiety. Based on these findings and evidence that two transmembrane arginines are important in binding, we developed a three-dimensional model of the TRH receptor binding pocket using molecular modeling and simulation programs. The model places the binding pocket for TRH within the transmembrane domains of the receptor and predicts that multiple hydrogen-bonding interactions are involved in binding TRH. To our knowledge, this is the first model, at an atomic level of detail, of the interaction of a peptide ligand with a GTP-binding protein-coupled receptor.

Source: Journal of Biological Chemistry

DOI: 10.1016/s0021-9258(17)31524-7

Authors: J.H. Perlman, L. Laakkonen, R. Osman, M.C. Gershengorn

Institutions: City University of New York, Cornell University, Icahn School of Medicine at Mount Sinai

Language: English

Topic: Receptor Mechanisms and Signaling

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: hybrid

Estimated APC paid: $3,430

Funders: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases