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    Molecular dynamics characterization of five pathogenic factor X mutants associated with decreased catalytic activity

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    Type
    Article
    Authors
    Abdel-Azeim, Safwat cc
    Oliva, Romina M.
    Chermak, Edrisse cc
    De Cristofaro, Raimondo
    Cavallo, Luigi cc
    KAUST Department
    Chemical Science Program
    KAUST Catalysis Center (KCC)
    Physical Science and Engineering (PSE) Division
    Date
    2014-10-24
    Online Publication Date
    2014-10-24
    Print Publication Date
    2014-11-11
    Permanent link to this record
    http://hdl.handle.net/10754/563850
    
    Metadata
    Show full item record
    Abstract
    Factor X (FX) is one of the major players in the blood coagulation cascade. Upon activation to FXa, it converts prothrombin to thrombin, which in turn converts fibrinogen into fibrin (blood clots). FXa deficiency causes hemostasis defects, such as intracranial bleeding, hemathrosis, and gastrointestinal blood loss. Herein, we have analyzed a pool of pathogenic mutations, located in the FXa catalytic domain and directly associated with defects in enzyme catalytic activity. Using chymotrypsinogen numbering, they correspond to D102N, T135M, V160A, G184S, and G197D. Molecular dynamics simulations were performed for 1.68 μs on the wild-type and mutated forms of FXa. Overall, our analysis shows that four of the five mutants considered, D102N, T135M, V160A, and G184S, have rigidities higher than those of the wild type, in terms of both overall protein motion and, specifically, subpocket S4 flexibility, while S1 is rather insensitive to the mutation. This acquired rigidity can clearly impact the substrate recognition of the mutants.
    Citation
    Abdel-Azeim, S., Oliva, R., Chermak, E., De Cristofaro, R., & Cavallo, L. (2014). Molecular Dynamics Characterization of Five Pathogenic Factor X Mutants Associated with Decreased Catalytic Activity. Biochemistry, 53(44), 6992–7001. doi:10.1021/bi500770p
    Sponsors
    Research reported in this publication was supported by the King Abdullah University of Science and Technology.
    Publisher
    American Chemical Society (ACS)
    Journal
    Biochemistry
    DOI
    10.1021/bi500770p
    PubMed ID
    25313940
    ae974a485f413a2113503eed53cd6c53
    10.1021/bi500770p
    Scopus Count
    Collections
    Articles; Physical Science and Engineering (PSE) Division; Chemical Science Program; KAUST Catalysis Center (KCC)

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