Molecular dynamics characterization of five pathogenic factor X mutants associated with decreased catalytic activity
Type
ArticleKAUST Department
Chemical Science ProgramKAUST Catalysis Center (KCC)
Physical Science and Engineering (PSE) Division
Date
2014-10-24Online Publication Date
2014-10-24Print Publication Date
2014-11-11Permanent link to this record
http://hdl.handle.net/10754/563850
Metadata
Show full item recordAbstract
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/bi500770pSponsors
Research reported in this publication was supported by the King Abdullah University of Science and Technology.Publisher
American Chemical Society (ACS)Journal
BiochemistryPubMed ID
25313940ae974a485f413a2113503eed53cd6c53
10.1021/bi500770p
Scopus Count
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