1hbt | pdb_00001hbt
Human alpha-thrombin complexed with a peptidyl pyridinium methyl ketone containing bivalent inhibitor
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] 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 PubMedThe crystal structure of a complex between a bivalent peptidyl pyridinium methyl ketone inhibitor and human alpha-thrombin has been solved and refined at 2.0 A to an R factor of 0.18. The inhibitor, (D)cyclohexylalanine-Pro-Arg-(CH2N+C5H4CH2CO)-(Gly)4-Asp- Tyr-Glu-Pro-Ile-Pro-Glu-Glu-Ala-cyclo-hexylalanine-(D)Glu (coded P596), which forms a reversible covalent complex with thrombin, is highly potent with a Ki = 4.6 +/- 1.0 x 10(-14) M, lower than that of recombinant hirudin. The N-terminal, active-site-directed portion of the inhibitor is linked to the fibrinogen recognition exosite binding portion by a tetraglycine segment. The strong electron-withdrawing effect provided by the permanent positive charge on the pyridinium nitrogen makes the arginyl carbonyl carbon more susceptible to nucleophilic attack. In the crystal, a covalent P596-thrombin complex is observed. The electron density surrounding the active site portion and the pyridinium of the inhibitor is very well defined, clearly showing the existence of a covalent bond between the Ser195 O gamma and the now tetrahedral carbon of the inhibitor. The decreased binding ability of thrombin inhibitors containing N-terminal acetylation is discussed as is the effect of replacing the P3 (D)phenylalanine with (D)cyclohexylalanine. The electron density surrounding the remainder of the inhibitor is generally well defined, the exceptions being the C-terminal (D)Glu, the highly flexible tetraglycine linker, and some of the solvent-directed side chains.(ABSTRACT TRUNCATED AT 250 WORDS) Crystal structure of a peptidyl pyridinium methyl ketone inhibitor with thrombin.,Rehse PH, Steinmetzer T, Li Y, Konishi Y, Cygler M Biochemistry. 1995 Sep 12;34(36):11537-44. PMID:7547884[16] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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