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The role of conserved water molecules in the catalytic domain of protein kinases |
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| Authors: | James D. R. Knight Donald Hamelberg J. Andrew McCammon Rashmi Kothary |
| Affiliation: | 1. Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6;2. The University of Ottawa Centre for Neuromuscular Disease, Ottawa, Ontario, Canada K1H 8M5;3. Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5;4. Department of Chemistry, Georgia State University, Atlanta, Georgia 30302‐4098;5. Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California 92093‐0365;6. Center for Theoretical Biological Physics, University of California San Diego, La Jolla, California 92093‐0365;7. Howard Hughes Medical Institute, University of California San Diego, La Jolla, California 92093‐0365;8. Department of Pharmacology, University of California San Diego, La Jolla, California 92093‐0365;9. Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5 |
| Abstract: | Protein kinases are essential signaling molecules with a characteristic bilobal shape that has been studied for over 15 years. Despite the number of crystal structures available, little study has been directed away from the prototypical functional elements of the kinase domain. We have performed a structural alignment of 13 active‐conformation kinases and discovered the presence of six water molecules that occur in conserved locations across this group of diverse kinases. Molecular dynamics simulations demonstrated that these waters confer a great deal of stability to their local environment and to a key catalytic residue. Our results highlight the importance of novel elements within the greater kinase family and suggest that conserved water molecules are necessary for efficient kinase function. Proteins 2009. © 2009 Wiley‐Liss, Inc. |
| Keywords: | free energy hydrogen bonding molecular dynamics protein stability structural alignment |