STRUCTURE MODELING OF HUMAN GPCRS AND DEVELOPMENT OF GPCR-TASSER

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. G protein coupled receptors (GPCRs) comprise the largest family of integral membrane proteins and are responsible for transduction of physiological & chemical signals into a cellular response. Malfunctioning of these proteins frequently causes a diseased condition, making them an important class of drug targets. However, structure-based drug design has been hampered by the lack of atomic-level protein structure information for GPCRs. Until now, only two of the GPCR structures, bovine rhodopsin(1) and 2-adrenergic receptor(2) have been solved. Previously, we employed TASSER (Threading ASSEmbly Refinement) algorithm (3) to generate structure prediction for 907 putative GPCRs in human genome (http://cssb.biology.gatech.edu/skolnick/files/gpcr/gpcr.html). Because TASSER uses a reduced Ca and side chain center of mass based protein models, most of these GPCRs models are estimated to have a root mean square deviation (RMSD) from native in the range of 3-6 for the backbone Ca atoms an accuracy useful for topology analysis and some level of biological function inference (4). The proposed study seeks to develop new computational methodologies for the generation of high resolution GPCR models using a composite GPCR specific and I-TASSER potential.This composite potential would include a knowledge based potential derived from literature and experimental data of GPCRs and also include a hydrophobic moment term for proper orientation of TM-helix. Modeling incorporated with experimental constraints will significantly enhance the biological usefulness of these models. References: (1) Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE, Yamamoto M, Miyano M. Crystal structure of rhodopsin: A G proteincoupled receptor. Science 2000;289(5480):739-745. (2) Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC. High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor. Science 2007;318(5854):1258-1265. (3) Zhang Y, Skolnick J. Automated structure prediction of weakly homologous proteins on a genomic scale. Proceedings of the National Academy of Sciences of the United States of America 2004;101:7594-7599. (4) Zhang Y, Devries ME, Skolnick J. Structure modeling of all identified G protein-coupled receptors in the human genome. PLoS Comput Biol 2006;2(2):e13