A MODEL OF THE THYROTROPIN-RELEASING-HORMONE (TRH) RECEPTOR-BINDING POCKET - EVIDENCE FOR A 2ND DIRECT INTERACTION BETWEEN TRANSMEMBRANE HELIX-3 AND TRH

The receptor for thyrotropin-releasing hormone (TRH) is a member of th e seven-transmembrane-spanning, GTP-binding protein-coupled receptor f amily. We showed that tyrosine at position 106 in transmembrane helix 3 of the TRH receptor directly binds the ring carbonyl of the pyroglut amyl 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, 1 610-1613). We now show that asparagine at position 110 of transmembran e helix 3 directly interacts with the ring N-H of the TRH pyroglutamyl moiety. Based on these findings and evidence that two transmembrane a rginines are important in binding, we developed a three-dimensional mo del of the TRH receptor binding pocket using molecular modeling and si mulation programs. The model places the binding pocket for TRH within the transmembrane domains of the receptor and predicts that multiple h ydrogen-bonding interactions are involved in binding TRH. To our knowl edge, this is the first model, at an atomic level of detail, of the in teraction of a peptide ligand with a GTP-binding protein-coupled recep tor.