GPCRs: an update on structural approaches to drug discovery |
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| Institution: | 1. School of Optoelectronics Science and Engineering, Huazhong University of Science and Technology, Wuhan 430074, China;2. Hubei Collaborative Innovation Center for High-Efficiency Utilization of Solar Energy and Hubei University of Technology, Wuhan 430074, China;3. AOV Energy Inc.,Wuhan 430074,China;1. Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan;2. Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan;3. Quantum Beam Science Directorate, Japan Atomic Energy Research Agency, Kyoto, Japan;1. Institute of Animal Physiology and Genetics CAS, v.v.i., Brno, Czech Republic;2. Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic;3. Department of Physiology, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic;1. Department of Pulmonary Diseases, Isala, Zwolle, The Netherlands;2. University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases, and Groningen Research Institute for Asthma and COPD GRIAC, Groningen, The Netherlands |
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| Abstract: | G-protein-coupled receptors (GPCRs) are a major opportunity for drug discovery in the post-genomic era. There are thought to be more than 500 therapeutically relevant GPCRs out of a total of over 700 identified to date, although only one, rhodopsin, has been the subject of a full 3D X-ray crystallography study. Two structurally related proteins, bacteriorhodopsin and sensory rhodopsin, which are not GPCRs but are part of the seven-helix membrane receptor family, have also been the subject of X-ray crystallographic studies and have been used in GPCR modeling studies. The significant differences between these rhodopsin structures, the relatively low sequence homology between individual GPCRs, and some difficulties in rationalizing point-mutation data suggests that homology-based molecular modeling alone will not provide the accurate structural information on individual receptors required for ligand design and in silico screening. In the absence of such structural information, several approaches can be used to assist in the discovery of ligands. |
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