Molecular dynamics characterization of five pathogenic factor X mutants associated with decreased catalytic activity
KAUST DepartmentChemical Science Program
KAUST Catalysis Center (KCC)
Physical Science and Engineering (PSE) Division
Online Publication Date2014-10-24
Print Publication Date2014-11-11
Permanent link to this recordhttp://hdl.handle.net/10754/563850
MetadataShow full item record
AbstractFactor 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.
CitationAbdel-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
SponsorsResearch reported in this publication was supported by the King Abdullah University of Science and Technology.
PublisherAmerican Chemical Society (ACS)
- A recurrent Gly43Asp substitution in coagulation Factor X rigidifies its catalytic pocket and impairs catalytic activity and intracellular trafficking.
- Authors: Menegatti M, Vangone A, Palla R, Milano G, Cavallo L, Oliva R, De Cristofaro R, Peyvandi F
- Issue date: 2014 Mar
- Characterization of a homozygous Gly11Val mutation in the Gla domain of coagulation factor X.
- Authors: Chafa O, Tagzirt M, Tapon-Bretaudière J, Reghis A, Fischer AM, LeBonniec BF
- Issue date: 2009 May
- Exploration of conformational transition in the aryl-binding site of human FXa using molecular dynamics simulations.
- Authors: Wang JF, Hao P, Li YX, Dai JL, Li X
- Issue date: 2012 Jun
- Profiling the structural determinants for the selectivity of representative factor-Xa and thrombin inhibitors using combined ligand-based and structure-based approaches.
- Authors: Bhunia SS, Roy KK, Saxena AK
- Issue date: 2011 Aug 22
- The Disulfide Bond between Cys22 and Cys27 in the Protease Domain Modulate Clotting Activity of Coagulation Factor X.
- Authors: Li F, Chen C, Qu SY, Zhao MZ, Xie X, Wu X, Li L, Wang X, Ding Q, Xu Q, Wei DQ, Wu W
- Issue date: 2019 Jun