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    Insight the C-Site Pocket Conformational Changes Responsible for Sirtuin 2 Activity Using Molecular Dynamics Simulations

    196147_105693_79325.pdf (1.769Mb)
    Access Status
    Open access
    Authors
    Sakkiah, Sugunadevi
    Arooj, Mahreen
    Ping Cao, Guang
    Woo Lee, Keun
    Date
    2013
    Type
    Journal Article
    
    Metadata
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    Citation
    Sakkiah, Sugunadevi and Arooj, Mahreen and Ping Cao, Guang and Woo Lee, Keun. 2013. Insight the C-Site Pocket Conformational Changes Responsible for Sirtuin 2 Activity Using Molecular Dynamics Simulations. PLoS ONE. 8 (3): e59278.
    Source Title
    PLoS ONE
    DOI
    10.1371/journal.pone.0059278
    ISSN
    19326203
    Remarks

    This article is published under the Open Access publishing model and distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0/ Please refer to the licence to obtain terms for any further reuse or distribution of this work.

    URI
    http://hdl.handle.net/20.500.11937/3869
    Collection
    • Curtin Research Publications
    Abstract

    Sirtuin belongs to a family of typical histone deacetylase which regulates the fundamental cellular biological processes including gene expression, genome stability, mitosis, nutrient metabolism, aging, mitochondrial function, and cell motility. Michael et. al. reported that B-site mutation (Q167A and H187A) decreased the SIRT2 activity but still the structural changes were not reported. Hence, we performed 5 ns molecular dynamics (MD) simulation on SIRT2 Apo-form and complexes with substrate/NAD+ and inhibitor of wild type (WT), Q167A, and H187A. The results revealed that the assembly and disassembly of C-site induced by presence of substrate/NAD+ and inhibitor, respectively. This assembly and disassembly was mainly due to the interaction between the substrate/NAD+ and inhibitor and F96 and the distance between F96 and H187 which are present at the neck of the C-site. MD simulations suggest that the conformational change of L3 plays a major role in assembly and disassembly of C-site. Our current results strongly suggest that the distinct conformational change of L3 as well as the assembly and disassembly of C-site plays an important role in SIRT2 deacetylation function. Our study unveiled the structural changes of SIRT2 in presence of NAD+ and inhibitor which should be helpful to improve the inhibitory potency of SIRT2.

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