The Conformational Dynamics and Molecular Mechanism of KstR

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dc.contributor.advisor Lott, S en
dc.contributor.advisor Allison, J en A Razzak, Ali en 2018-07-11T01:57:12Z en 2018 en
dc.identifier.uri en
dc.description Full text is available to authenticated members of The University of Auckland only. en
dc.description.abstract Mycobacterium tuberculosis (Mtb) contains a remarkable array of lipid and cholesterol metabolic processes. The expression of genes involved in cholesterol degradation is controlled by KstR, a transcriptional repressor in Mycobacteria. KstR has a pivotal role in facilitating the persistence of Mtb within human hosts through the regulation of cholesterol metabolisation. KstR activity can be reduced to a three state model. The first state is apo KstR. The second state is DNA-bound KstR, presenting a contracted shape compared to apo that is structurally restrained due to its association with DNA. The third state is ligand-bound KstR, where it associates with metabolites produced early in the cholesterol degradation pathway, which bind to the ligand binding pocket. Ligand-bound KstR is more structurally constrained than apo KstR, locking KstR into a wider architecture, and preventing DNA binding. Modulation of the conformation of KstR is essential in informing its association with DNA, and thereby its ability to repress cholesterol degradation genes. By starting with the resolved structures of apo KstR, DNA-bound KstR, and ligand-bound KstR, the activity of KstR was modelled through computational simulations which revealed potential KstR conformational trajectories. Molecular dynamics simulations have provided insight into which regions of KstR change conformation, and the extent of conformational deviation that different states of KstR can take on. This demonstrated distinct conformational paths between apo KstR, DNA-bound KstR, and ligand-bound KstR. This research has contributed evidence towards a mechanism of action of KstR. en
dc.publisher ResearchSpace@Auckland en
dc.relation.ispartof Masters Thesis - University of Auckland en
dc.relation.isreferencedby UoA99265077211302091 en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights Restricted Item. Available to authenticated members of The University of Auckland. en
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dc.rights.uri en
dc.title The Conformational Dynamics and Molecular Mechanism of KstR en
dc.type Thesis en Biological Science en The University of Auckland en Masters en
dc.rights.holder Copyright: The author en
pubs.elements-id 747591 en
pubs.record-created-at-source-date 2018-07-11 en

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