SER195ALA MUTANT OF HUMAN THROMBIN COMPLEXED WITH FIBRINOPEPTIDE A (7-16)
[THRB_HUMAN] Defects in F2 are the cause of factor II deficiency (FA2D) [MIM:613679]. It is a very rare blood coagulation disorder characterized by mucocutaneous bleeding symptoms. The severity of the bleeding manifestations correlates with blood factor II levels.            Genetic variations in F2 may be a cause of susceptibility to ischemic stroke (ISCHSTR) [MIM:601367]; also known as cerebrovascular accident or cerebral infarction. A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors. Defects in F2 are the cause of thrombophilia due to thrombin defect (THPH1) [MIM:188050]. It is a multifactorial disorder of hemostasis characterized by abnormal platelet aggregation in response to various agents and recurrent thrombi formation. Note=A common genetic variation in the 3-prime untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increased risk of venous thrombosis. Defects in F2 are associated with susceptibility to pregnancy loss, recurrent, type 2 (RPRGL2) [MIM:614390]. A common complication of pregnancy, resulting in spontaneous abortion before the fetus has reached viability. The term includes all miscarriages from the time of conception until 24 weeks of gestation. Recurrent pregnancy loss is defined as 3 or more consecutive spontaneous abortions.
[THRB_HUMAN] Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostasis, inflammation and wound healing.
Publication Abstract from PubMed
The Ser195Ala mutant of human alpha-thrombin was complexed with fibrinopeptide A(7-22) (FPA) in an effort to describe the (P1'-P6') post-cleavage binding subsites of the fibrinogen-recognition exosite and define more clearly the nature of the Michaelis complex and the scissile peptide bond bound at the catalytic site. The thrombin mutant, however, has residual catalytic activity and proteolysis occurred at the Arg16-Gly17 bond. Thus, the structure of the thrombin complex determined was that of FPA(7-16) bound at the active site, which is very similar to the ternary FPA(7-16)cmk-human thrombin-hirugen complex (r.m.s.d. approximately 0.4 A; Stubbs et al. , 1992). It is further shown by subsidiary experiments that the cleavage is the result of residual catalytic activity of the altered catalytic machinery.
Structure of the Ser195Ala mutant of human alpha--thrombin complexed with fibrinopeptide A(7--16): evidence for residual catalytic activity.,Krishnan R, Sadler JE, Tulinsky A Acta Crystallogr D Biol Crystallogr. 2000 Apr;56(Pt 4):406-10. PMID:10739913
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.