Reeves, Philip - University of Essex - School of Biological Sciences

个人简介

2005–present. Lecturer, School of Biological Sciences, University of Essex, Colchester, UK. 1994-2005. Postdoctoral Research Fellow/Research Scientist, Department of Biology, MIT, Cambridge (USA). Laboratory of H. Gobind Khorana. 1991-1994. Postdoctoral Research Fellow, Department of Biological Sciences, University of Warwick, Coventry, UK. 1987-1991. PhD. in Molecular biology of protein secretion. University of Warwick. Coventry, UK. Supervisor George Salmond 1986-1987. Research Technician Department of Biological Sciences, University of Warwick, Coventry, UK. 1983-1986. BSc. (Hons) Microbiology and Microbial Technology. University of Warwick, Coventry, UK.

研究领域

Structural properties and activation mechanism of rhodopsin, the dim-light human photoreceptor. (details) Biosynthesis and cellular targeting of G-protein coupled receptors (GPCRs). Development of gene expression systems for large-scale production and purification of membrane proteins. (details). Molecular mechanisms of Retinitis Pigmentosa caused by inherited mutations in rhodopsin My research focuses on structure and function analysis of membrane proteins with emphasis on the G-Protein Coupled Receptor (GPCR) family. GPCRs are the largest family of membrane proteins in eukaryotes comprising 1-5% of the genome. All GPCRs have seven transmembrane spanning helices connected by three intracellular and three extracellular loops. GPCRs mediate signal transduction in response to diverse extracellular signals including odourants, peptides hormones and light and as a consequence they perform crucial roles throughout biology (e.g. development, vision, smell, cardiovascular control, neurobiology, endocrinology). GPCR malfunction is implicated in numerous diseases such as cardiovascular disease, cancer, endocrine disorders and blindness. Significantly, GPCRs are excellent cellular targets for pharmaceutical intervention and about 50% of current drugs are aimed at GPCR processes. Rhodopsin is a prototypical GPCR. Located in the discs of rod photoreceptor cells it mediates vision in response to light under twilight conditions. Our research on rhodopsin focusses on two main areas: (1) folding, structure and function and (2) mutations that give rise to Retinitis pigmentosa, an incurable form of inherited blindness Determination of the active state rhodopsin structure is a key focus and this work is in collaboration with Professor Steven Smith’s group in the USA where Solid State NMR is performed (http://www.stonybrook.edu/biochem/smith/index.html). We also use rhodopsin as a model system to better understand protein folding and dynamics in membrane proteins. We are also investigating the mechanism of ligand exit and entry in rhodopsin. Numerous mutations in rhodopsin result in Autosomal Dominant Retinitis Pigmentosa (ADRP), a common inherited disease of the retina that leads to progressive vision loss and ultimately blindness in that starts in young aldulthood. There is currently no cure for Retinitis Pigmentosa. Our aim is to understand at the molecular level the defects in these malfunctioning rhodopsin ADRP mutants that ultimately trigger destruction of the entire retina. This will pave the way for identification of new targets for therapeutic intervention to slow down or halt disease progression. Our research into ADRP is in collaboration with Professor Mike Cheetham of the Department of Ophthalmology at UCL. (https://iris.ucl.ac.uk/iris/browse/profile?upi=MECHE52)

近期论文

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1. Taddese, B., Upton, G. J. G., Bailey, G. R., Jordan, S. R. D., Abdulla, N. Y., Reeves, P. J., and Reynolds, C. A. (2014) Do Plants Contain G Protein-Coupled Receptors? Plant Physiology 164, 287-307. 2. Pope, A., Eilers, M., Reeves, P. J., and Smith, S. O. (2014) Amino acid conservation and interactions in rhodopsin: Probing receptor activation by NMR spectroscopy. Biochimica Et Biophysica Acta-Bioenergetics 1837, 683-693. 3. Chintapalli, S. V., Illingworth, C. J. R., Upton, G. J. G., Sacquin-Mora, S., Reeves, P. J., Mohammedali, H. S., and Reynolds, C. A. (2014) Assessing the effect of dynamics on the closed-loop protein-folding hypothesis. Journal of the Royal Society Interface 11 4. Vohra, S., Taddese, B., Conner, A. C., Poyner, D. R., Hay, D. L., Barwell, J., Reeves, P. J., Upton, G. J. G., and Reynolds, C. A. (2013) Similarity between class A and class B G-protein-coupled receptors exemplified through calcitonin gene-related peptide receptor modelling and mutagenesis studies. Journal of the Royal Society Interface 10 5. Opefi, C. A., South, K., Reynolds, C. A., Smith, S. O., and Reeves, P. J. (2013) Retinitis Pigmentosa Mutants Provide Insight into the Role of the N-terminal Cap in Rhodopsin Folding, Structure, and Function. Journal of Biological Chemistry 288, 33912-33926 6. Goncalves, J., Eilers, M., South, K., Opefi, C. A., Laissue, P., Reeves, P. J., and Smith, S. O. (2013) Magic Angle Spinning Nuclear Magnetic Resonance Spectroscopy of G Protein- Coupled Receptors. in G Protein Coupled Receptors: Modeling, Activation, Interactions and Virtual Screening (Conn, P. M. ed.). pp 365-389 7. Eilers, M., Goncalves, J. A., Abuja, S., Kirkup, C., Hirshfeld, A., Simmerling, C., Reeves, P. J., Sheves, M., and Smith, S. O. (2012) Structural Transitions of Transmembrane Helix 6 in the Formation of Metarhodopsin I. Journal of Physical Chemistry B 116, 10477-10489 8. Arakawa, M., Chakraborty, R., Upadhyaya, J., Eilers, M., Reeves, P. J., Smith, S. O., and Chelikani, P. (2011) Structural and functional roles of small group-conserved amino acids present on helix-H7 in the beta(2)-adrenergic receptor. Biochimica Et Biophysica Acta- Biomembranes 1808, 1170-1178 9. Hornak, V., Ahuja, S., Eilers, M., Goncalves, J. A., Sheves, M., Reeves, P. J., and Smith, S. O. (2010) Light Activation of Rhodopsin: Insights from Molecular Dynamics Simulations Guided by Solid-State NMR Distance Restraints. Journal of Molecular Biology 396, 510-527 10. Goncalves, J. A., South, K., Ahuja, S., Zaitseva, E., Opefi, C. A., Eilers, M., Vogel, R., Reeves, P. J., and Smith, S. O. (2010) Highly conserved tyrosine stabilizes the active state of rhodopsin. Proceedings of the National Academy of Sciences of the United States of America 107, 19861-19866 11. Chintapalli, S. V., Yew, B. K., Illingworth, C. J. R., Upton, G. J. G., Reeves, P. J., Parkes, K. E. B., Snell, C. R., and Reynolds, C. A. (2010) Closed Loop Folding Units from Structural Alignments: Experimental Foldons Revisited. Journal of Computational Chemistry 31, 2689-2701 12. Ahuja, S., Hornak, V., Yan, E. C. Y., Syrett, N., Goncalves, J. A., Hirshfeld, A., Ziliox, M., Sakmar, T. P., Sheves, M., Reeves, P. J., Smith, S. O., and Eilers, M. (2009) Helix movement is coupled to displacement of the second extracellular loop in rhodopsin activation. Nature Structural & Molecular Biology 16, 168-175 13. Ahuja, S., Crocker, E., Eilers, M., Hornak, V., Hirshfeld, A., Ziliox, M., Syrett, N., Reeves, P. J., Khorana, H. G., Sheves, M., and Smith, S. O. (2009) Location of the Retinal Chromophore in the Activated State of Rhodopsin. Journal of Biological Chemistry 284, 10190-10201 14. Takayama, H., Chelikani, P., Reeves, P. J., Zhang, S., and Khorana, H. G. (2008) High-Level Expression, Single-Step Immunoaffinity Purification and Characterization of Human Tetraspanin Membrane Protein CD81. Plos One 3 15. Vohra, S., Chintapalli, S. V., Illingworth, C. J. R., Reeves, P. J., Mullineaux, P. M., Clark, H. S. X., Dean, M. K., Upton, G. J. G., and Reynolds, C. A. (2007) Computational studies of family a and family B GPCRs. Biochemical Society Transactions 35, 749-754 16. McKibbin, C., Toye, A. M., Reeves, P. J., Khorana, H. G., Edwards, P. C., Villa, C., and Booth, P. J. (2007) Opsin stability and folding: The role of Cys185 and abnormal disulfide bond formation in the intradiscal domain. Journal of Molecular Biology 374, 1309-1318 17. McKibbin, C., Farmer, N. A., Jeans, C., Reeves, P. J., Khorana, H. G., Wallace, B. A., Edwards, P. C., Villa, C., and Booth, P. J. (2007) Opsin stability and folding: Modulation by phospholipid bicelles. Journal of Molecular Biology 374, 1319-1332 18. Chelikani, P., Hornak, V., Eilers, M., Reeves, P. J., Smith, S. O., RajBhandary, U. L., and Khorana, H. G. (2007) Role of group-conserved residues in the helical core of beta(2)-adrenergic receptor. Proceedings of the National Academy of Sciences of the United States of America 104, 7027-7032 19. Zhao, X., Nagai, Y., Reeves, P. J., Kiley, P., Khorana, H. G., and Zhang, S. (2006) Designer short peptide surfactants stabilize G protein-coupled receptor bovine rhodopsin. Proceedings of the National Academy of Sciences of the United States of America 103, 17707-17712 20. Kota, P., Reeves, P. J., RajBhandary, U. L., and Khorana, H. G. (2006) Opsin is present as dimers in COS1 cells: Identification of amino acids at the dimeric interface. Proceedings of the National Academy of Sciences of the United States of America 103, 3054-3059