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Structural debilitation of mutation G322D associated with MSH2 and their role in triple negative breast cancer.
Journal of Biomolecular Structure & Dynamics 2019 Februrary 27
The missense mutation in the mismatch repair gene MSH2 underlies in several hereditary cancers. In this study, we have detailed the disruptive mutation of G322D that overtly pathogenic and clinically relevant to the triple negative breast cancer (TNBC) on the basis of structural aspect to untangle the unknown factors. We systematically evaluated the conformational changes that undergo upon mutation from the annotation of intra-residual contacts, secondary structural arrangements and fold recognition through molecular dynamics simulation. At first, we interpreted the total of 88 intra-molecular interaction which is required minimally to maintain the native structural architecture. Adequately, the molecular dynamics approach is well contributed towards structural modification that takes places in C-terminal linking 290-294(L20) , 339-347(L23-T16- α9-T17) and 373-395(α12-T19-20-L26-T21-L27-T22) in contrast to native 290-294(β8) , 339-347(T20-α9-T21-α10) , 373-395(α12-T19-20-L26-T21-L27-T22) provides a straightforward evidence that is underpinning destabilization and protein misfolding. Eventually, we have highlighted the structural debilitation of G322D in the core region of 303-309 L23-T18-α6 - L21- α8 , and 326-330 α7-T19-L25 -α9 notably the connecting elements of secondary structural propensity (loop-helix) in folding pack were completely abrupted which helps to keep native form. Essentially, the information gained in our study on residual interaction and conformational transitions in the structure of mutant MSH2 provides valuable insights to understand the clues of functional behavior and also pave the way to frame suitable and improved therapeutical targets.
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