1hlt
From Proteopedia
THE STRUCTURE OF A NONADECAPEPTIDE OF THE FIFTH EGF DOMAIN OF THROMBOMODULIN COMPLEXED WITH THROMBIN
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] [TRBM_HUMAN] Defects in THBD are the cause of thrombophilia due to thrombomodulin defect (THPH12) [MIM:614486]. A hemostatic disorder characterized by a tendency to thrombosis.[15] [16] [17] Defects in THBD are a cause of susceptibility to hemolytic uremic syndrome atypical type 6 (AHUS6) [MIM:612926]. An atypical form of hemolytic uremic syndrome. It is a complex genetic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure and absence of episodes of enterocolitis and diarrhea. In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease. Note=Susceptibility to the development of atypical hemolytic uremic syndrome can be conferred by mutations in various components of or regulatory factors in the complement cascade system. Other genes may play a role in modifying the phenotype.[18] [19] 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.[20] [TRBM_HUMAN] Thrombomodulin is a specific endothelial cell receptor that forms a 1:1 stoichiometric complex with thrombin. This complex is responsible for the conversion of protein C to the activated protein C (protein Ca). Once evolved, protein Ca scissions the activated cofactors of the coagulation mechanism, factor Va and factor VIIIa, and thereby reduces the amount of thrombin generated. 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 crystallographic structure has been determined of a complex between a nonadecapeptide from the fifth epidermal growth factor (EGF5) domain of human thrombomodulin and human D-PheProArg-alpha-thrombin. The peptide corresponds to amino acid residues Glu408-Glu426 of thrombomodulin and contains the third disulfide loop of EGF5 and its linker to EGF6. The structure was refined at 3.0-A resolution to an R-value of 0.146. There are two thrombin molecules in the asymmetric unit, and the structure in the crystal is a 2:1 thrombin complex. The folding of the peptide corresponds closely to the third disulfide loop of EGF2 of factor Xa (rms delta = 1.0 A). The peptide is squeezed between cofacial electropositive fibrinogen recognition exo sites of the two thrombin molecules. Since the peptide has a total of seven aspartic and glutamic acid residues, the principal binding interaction with thrombin is electrostatic. A major hydrophobic association, which is highly directional in such a pronounced electrostatic environment, involves a TyrIleLeu triplet of the peptide and Phe34, Leu65, Tyr76, and Ile82 (chymotrypsinogen numbering) of one thrombin molecule. The tyrosine of the peptide is sandwiched between the thrombin aromatic rings and is most likely the prime source of the specificity of the thrombomodulin-thrombin interaction. Structure of a nonadecapeptide of the fifth EGF domain of thrombomodulin complexed with thrombin.,Mathews II, Padmanabhan KP, Tulinksy A, Sadler JE Biochemistry. 1994 Nov 22;33(46):13547-52. PMID:7947765[21] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||
