Structure-dynamics-function relation of metalloproteins : coupling magnetic resonance spectroscopy and simulation
Dynamics of proteins are increasingly recognised as key features as they can contribute to the function of the protein. Structural dynamics manifest as protein folding, protein domain movement and small allosteric responses. Hence, investigating and understanding atomistic motions in proteins to elu...
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University College London (University of London)
2015
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| Online Access: | http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.639705 |
| Summary: | Dynamics of proteins are increasingly recognised as key features as they can contribute to the function of the protein. Structural dynamics manifest as protein folding, protein domain movement and small allosteric responses. Hence, investigating and understanding atomistic motions in proteins to elucidate their implication in protein function mark a crucial paradigm shift from a structure-function relation to a structure-dynamics-function relation. The human histone deacetylase 8 is a key hydrolase in gene regulation and has been identified as a drug target for the treatment of several cancers. I used molecular dynamics simulations to propose a mechanism by which dynamic loop interactions can influence the activity of the human histone deacetylase 8. Subsequently I substantiated this hypothesis by using experimental techniques such as biochemical assays and single point mutations. Furthermore, I studied the structure and dynamics of the histone deacetylase 8 using nuclear magnetic resonance techniques. The proposed mechanism of loop interaction yields a mechanistic rationale for phenomena that could not be explained on a molecular level before. |
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