1h8d

X-ray structure of the human alpha-thrombin complex with a tripeptide phosphonate inhibitor.X-ray structure of the human alpha-thrombin complex with a tripeptide phosphonate inhibitor.

Structural highlights 1h8d is a 3 chain structure with sequence from Hirudo medicinalis and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: NonStd Res: Related: 1a2c, 1a3b, 1a3e, 1a46, 1a4w, 1a5g, 1a61, 1abi, 1abj, 1ad8, 1ae8, 1afe, 1aht, 1ai8, 1aix, 1awf, 1awh, 1ay6, 1b5g, 1b7x, 1ba8, 1bb0, 1bcu, 1bhx, 1bmm, 1bmn, 1bth, 1c1u, 1c1v, 1c1w, 1c4u, 1c4v, 1c4y, 1c5l, 1c5n, 1c5o, 1ca8, 1d3d, 1d3p, 1d3q, 1d3t, 1d4p, 1d6w, 1d9i, 1de7, 1dit, 1dm4, 1dwb, 1dwc, 1dwd, 1dwe, 1dx5, 1e0f, 1eoj, 1eol, 1fpc, 1fph, 1hag, 1hah, 1hai, 1hao, 1hap, 1hbt, 1hdt, 1hgt, 1hlt, 1hut, 1hxe, 1hxf, 1ihs, 1iht, 1lhc, 1lhd, 1lhe, 1lhf, 1lhg, 1nrn, 1nro, 1nrp, 1nrq, 1nrr, 1nrs, 1ppb, 1qbv, 1qhr, 1qj1, 1qj6, 1qj7, 1qur, 1tbz, 1thp, 1thr, 1ths, 1tmb, 1tmt, 1tmu, 1tom, 1uma, 1uvs, 1vr1, 2hgt, 2hnt, 2hpp, 2hpq, 2thf, 3hat, 3htc, 4htc, 4thn, 5gds, 7kme, 8kme Activity: Thrombin, with EC number 3.4.21.5 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum 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. 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. 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. [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. 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 PubMed X-ray crystallographic studies of human alpha-thrombin with a novel synthetic inhibitor, an acyl (alpha-aminoalkyl)phosphonate, reveal the existence of a pentacovalent phosphorus intermediate state. Crystal structures of the complex of alpha-thrombin with the phosphonate compound were determined independently using crystals of different ages. The first structure, solved from a crystal less than seven days old, showed a pentacoordinated phosphorus moiety. The second structure, determined from a crystal that was 12 weeks old, showed a tetracoordinated phosphorus moiety. In the first structure, a water molecule, made nucleophilic by coordination to His57 of alpha-thrombin, is bonded to the pentacoordinated phosphorus atom. Its position is approximately equivalent to that occupied by the water molecule responsible for hydrolytic deacylation during normal hydrolysis. The pentacoordinated phosphorus adduct collapses to give the expected pseudo tetrahedral complex, where the phosphorus atom is covalently bonded to Ser195 O(gamma). The crystallographic data presented here therefore suggest that the covalent bond formed between the inhibitor's phosphorus atom and O(gamma) of Ser195 proceeds via an addition-elimination mechanism, which involves the formation of a pentacoordinate intermediate. Inhibition of human alpha-thrombin by a phosphonate tripeptide proceeds via a metastable pentacoordinated phosphorus intermediate.,Skordalakes E, Dodson GG, Green DS, Goodwin CA, Scully MF, Hudson HR, Kakkar VV, Deadman JJ J Mol Biol. 2001 Aug 17;311(3):549-55. PMID:11493008 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Hirudin Thrombin

spinqualitylabelsall models 1h8d, resolution 1.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image