3jz1
From Proteopedia
Crystal structure of human thrombin mutant N143P in E:Na+ form
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 molecular mechanism of thrombin activation by Na(+) remains elusive. Its kinetic formulation requires extension of the classical Botts-Morales theory for the action of a modifier on an enzyme to correctly account for the contribution of the E*, E, and E:Na(+) forms. The extended scheme establishes that analysis of k(cat) unequivocally identifies allosteric transduction of Na(+) binding into enhanced catalytic activity. The thrombin mutant N143P features no Na(+)-dependent enhancement of k(cat) yet binds Na(+) with an affinity comparable to that of wild type. Crystal structures of the mutant in the presence and absence of Na(+) confirm that Pro(143) abrogates the important H-bond between the backbone N atom of residue 143 and the carbonyl O atom of Glu(192), which in turn controls the orientation of the Glu(192)-Gly(193) peptide bond and the correct architecture of the oxyanion hole. We conclude that Na(+) activates thrombin by securing the correct orientation of the Glu(192)-Gly(193) peptide bond, which is likely flipped in the absence of cation. Absolute conservation of the 143-192 H-bond in trypsin-like proteases and the importance of the oxyanion hole in protease function suggest that this mechanism of Na(+) activation is present in all Na(+)-activated trypsin-like proteases. Mutant N143P reveals how Na+ activates thrombin.,Niu W, Chen Z, Bush-Pelc LA, Bah A, Gandhi PS, Di Cera E J Biol Chem. 2009 Dec 25;284(52):36175-85. Epub 2009 Oct 21. PMID:19846563[16] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||||||
Categories: Human | Large Structures | Thrombin | Bah, A | Bush-Pelc, L A | Cera, E Di | Chen, Z | Gandhi, P S | Niu, W | Acute phase | Blood coagulation | Cleavage on pair of basic residue | Disease mutation | Disulfide bond | Gamma-carboxyglutamic acid | Glycoprotein | Hydrolase | Kringle | Protease | Secreted | Serine protease | Zymogen
