1hxf
From Proteopedia
HUMAN THROMBIN COMPLEX WITH HIRUDIN VARIANT
Structural highlights
Disease[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.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] 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.[13] 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.[14] Function[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.[15] [HIRV1_HIRME] Hirudin is a potent thrombin-specific protease inhibitor. It forms a stable non-covalent complex with alpha-thrombin, thereby abolishing its ability to cleave fibrinogen.[16] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedWhen Na+ binds to thrombin, a conformational change is induced that renders the enzyme kinetically faster and more specific in the activation of fibrinogen. Two Na+ binding sites have here been identified crystallographically by exchanging Na+ with Rb+. One is intermolecular, found on the surface between two symmetry-related thrombin molecules. Since it is not present in thrombin crystal structures having different crystal systems, the other Na+ site is the functionally relevant one. The second site has octahedral coordination with the carbonyl oxygen atoms of Arg221A and Lys224 and four conserved water molecules. It is located near Asp189 of the S1 specificity site in an elongated solvent channel (8 x 18 A) formed by four antiparallel beta-strands between Cys182-Cys191 and Val213-Tyr228. This channel, extending from the active site to the opposite surface of the enzyme, was first noted in the hirudin-thrombin structure and contains about 20 conserved water molecules linked together by a hydrogen bonding network that connects to the main chain of thrombin. Although the antiparallel beta-strand interactions of the functional Na+ binding site are the same in prethrombin2, the loops between the strands are very different, so that Asp189 and Arg221A are not positioned properly for either substrate or Na+ binding in prethrombin2. A water molecule with octahedral coordination has also been identified in factor Xa at the topologically equivalent Na+ site position of thrombin. Since activated protein C shows enhanced activity with monovalant cation binding, the same position is probably utilized by Na+. Since thrombin crystals could not be grown in the absence of Na+, the cation was leached from Na(+)-bound thrombin crystals by diffusion/exchange. Although both Na+ and their coordinating water molecules were removed from the Na+ binding sites, the remainder of the thrombin structure was, unexpectedly, the same. The lack of an allosteric change is most likely attributable to crystal packing effects. Thus, the structure of the slow form remains to be established crystallographically. The molecular environment of the Na+ binding site of thrombin.,Zhang E, Tulinsky A Biophys Chem. 1997 Jan 31;63(2-3):185-200. PMID:9108691[17] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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