Abstract
We employed the first principles computational method MembStruk and homology modeling techniques to predict the 3D structures of the human phenylthiocarbamide (PTC) taste receptor. This protein is a seven-transmembrane-domain G protein-coupled receptor that exists in two main forms worldwide, designated taster and nontaster, which differ from each other at three amino-acid positions. 3D models were generated with and without structural similarity comparison to bovine rhodopsin. We used computational tools (HierDock and ScanBindSite) to generate models of the receptor bound to PTC ligand to estimate binding sites and binding energies. In these models, PTC binds at a site distant from the variant amino acids, and PTC binding energy was equivalent for both the taster and nontaster forms of the protein. These models suggest that the inability of humans to taste PTC is due to a failure of G protein activation rather than decreased binding affinity of the receptor for PTC. Amino-acid substitutions in the sixth and seventh transmembrane domains of the nontaster form of the protein may produce increased steric hindrance between these two α-helices and reduce the motion of the sixth helix required for G protein activation.
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Acknowledgements
We thank Dr. Susan Sullivan and Dr. John Northup for helpful comments on the manuscript. This work was supported by NIDCD Z01-000046-04, and by NIH-BRGRO1-GM625523, NIH-R29AI40567, and NIH-HD36385. The computational facilities at the Materials and Process Simulation Center (MSC) were provided by a Shared University Research grant from International Business Machines and Defense University Research Instrumentation Program grants from the Army Research Office (ARO) and the Office of Naval Research (ONR). The facilities of the MSC are also supported by the Department of Energy-Advanced Simulation and Computing Program, National Science Foundation, Multidisciplinary Research Initiative - Army Research Office, Multidisciplinary Research Initiative - Office of Naval Research, General Motors, ChevronTexaco, Seiko-Epson, Beckman Institute, and Asahi Kasei.
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Floriano, W.B., Hall, S., Vaidehi, N. et al. Modeling the human PTC bitter-taste receptor interactions with bitter tastants. J Mol Model 12, 931–941 (2006). https://doi.org/10.1007/s00894-006-0102-6
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DOI: https://doi.org/10.1007/s00894-006-0102-6