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1h8d

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Revision as of 09:17, 10 January 2018

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, ProSAT

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 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^[17]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Wang W, Fu Q, Zhou R, Wu W, Ding Q, Hu Y, Wang X, Wang H, Wang Z. Prothrombin Shanghai: hypoprothrombinaemia caused by substitution of Gla29 by Gly. Haemophilia. 2004 Jan;10(1):94-7. PMID:14962227
↑ Board PG, Shaw DC. Determination of the amino acid substitution in human prothrombin type 3 (157 Glu leads to Lys) and the localization of a third thrombin cleavage site. Br J Haematol. 1983 Jun;54(2):245-54. PMID:6405779
↑ Rabiet MJ, Furie BC, Furie B. Molecular defect of prothrombin Barcelona. Substitution of cysteine for arginine at residue 273. J Biol Chem. 1986 Nov 15;261(32):15045-8. PMID:3771562
↑ Miyata T, Morita T, Inomoto T, Kawauchi S, Shirakami A, Iwanaga S. Prothrombin Tokushima, a replacement of arginine-418 by tryptophan that impairs the fibrinogen clotting activity of derived thrombin Tokushima. Biochemistry. 1987 Feb 24;26(4):1117-22. PMID:3567158
↑ Inomoto T, Shirakami A, Kawauchi S, Shigekiyo T, Saito S, Miyoshi K, Morita T, Iwanaga S. Prothrombin Tokushima: characterization of dysfunctional thrombin derived from a variant of human prothrombin. Blood. 1987 Feb;69(2):565-9. PMID:3801671
↑ Henriksen RA, Mann KG. Identification of the primary structural defect in the dysthrombin thrombin Quick I: substitution of cysteine for arginine-382. Biochemistry. 1988 Dec 27;27(26):9160-5. PMID:3242619
↑ Henriksen RA, Mann KG. Substitution of valine for glycine-558 in the congenital dysthrombin thrombin Quick II alters primary substrate specificity. Biochemistry. 1989 Mar 7;28(5):2078-82. PMID:2719946
↑ Miyata T, Aruga R, Umeyama H, Bezeaud A, Guillin MC, Iwanaga S. Prothrombin Salakta: substitution of glutamic acid-466 by alanine reduces the fibrinogen clotting activity and the esterase activity. Biochemistry. 1992 Aug 25;31(33):7457-62. PMID:1354985
↑ Morishita E, Saito M, Kumabashiri I, Asakura H, Matsuda T, Yamaguchi K. Prothrombin Himi: a compound heterozygote for two dysfunctional prothrombin molecules (Met-337-->Thr and Arg-388-->His). Blood. 1992 Nov 1;80(9):2275-80. PMID:1421398
↑ Iwahana H, Yoshimoto K, Shigekiyo T, Shirakami A, Saito S, Itakura M. Detection of a single base substitution of the gene for prothrombin Tokushima. The application of PCR-SSCP for the genetic and molecular analysis of dysprothrombinemia. Int J Hematol. 1992 Feb;55(1):93-100. PMID:1349838
↑ James HL, Kim DJ, Zheng DQ, Girolami A. Prothrombin Padua I: incomplete activation due to an amino acid substitution at a factor Xa cleavage site. Blood Coagul Fibrinolysis. 1994 Oct;5(5):841-4. PMID:7865694
↑ Degen SJ, McDowell SA, Sparks LM, Scharrer I. Prothrombin Frankfurt: a dysfunctional prothrombin characterized by substitution of Glu-466 by Ala. Thromb Haemost. 1995 Feb;73(2):203-9. PMID:7792730
↑ Casas JP, Hingorani AD, Bautista LE, Sharma P. Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls. Arch Neurol. 2004 Nov;61(11):1652-61. PMID:15534175 doi:61/11/1652
↑ Pihusch R, Buchholz T, Lohse P, Rubsamen H, Rogenhofer N, Hasbargen U, Hiller E, Thaler CJ. Thrombophilic gene mutations and recurrent spontaneous abortion: prothrombin mutation increases the risk in the first trimester. Am J Reprod Immunol. 2001 Aug;46(2):124-31. PMID:11506076
↑ Glenn KC, Frost GH, Bergmann JS, Carney DH. Synthetic peptides bind to high-affinity thrombin receptors and modulate thrombin mitogenesis. Pept Res. 1988 Nov-Dec;1(2):65-73. PMID:2856554
↑ Song X, Mo W, Liu X, Zhu L, Yan X, Song H, Dai L. The NMR solution structure of recombinant RGD-hirudin. Biochem Biophys Res Commun. 2007 Aug 17;360(1):103-8. Epub 2007 Jun 13. PMID:17585879 doi:10.1016/j.bbrc.2007.06.014
↑ Skordalakes E, Dodson GG, Green DS, Goodwin CA, Scully MF, Hudson HR, Kakkar VV, Deadman JJ. Inhibition of human alpha-thrombin by a phosphonate tripeptide proceeds via a metastable pentacoordinated phosphorus intermediate. J Mol Biol. 2001 Aug 17;311(3):549-55. PMID:11493008 doi:10.1006/jmbi.2001.4872

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1h8d"

@@ Line 1: / Line 1: @@
 ==X-ray structure of the human alpha-thrombin complex with a tripeptide phosphonate inhibitor.==
 <StructureSection load='1h8d' size='340' side='right' caption='[[1h8d]], [[Resolution|resolution]] 1.40&Aring;' scene=''>
@@ Line 7: / Line 8: @@
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1a2c|1a2c]], [[1a3b|1a3b]], [[1a3e|1a3e]], [[1a46|1a46]], [[1a4w|1a4w]], [[1a5g|1a5g]], [[1a61|1a61]], [[1abi|1abi]], [[1abj|1abj]], [[1ad8|1ad8]], [[1ae8|1ae8]], [[1afe|1afe]], [[1aht|1aht]], [[1ai8|1ai8]], [[1aix|1aix]], [[1awf|1awf]], [[1awh|1awh]], [[1ay6|1ay6]], [[1b5g|1b5g]], [[1b7x|1b7x]], [[1ba8|1ba8]], [[1bb0|1bb0]], [[1bcu|1bcu]], [[1bhx|1bhx]], [[1bmm|1bmm]], [[1bmn|1bmn]], [[1bth|1bth]], [[1c1u|1c1u]], [[1c1v|1c1v]], [[1c1w|1c1w]], [[1c4u|1c4u]], [[1c4v|1c4v]], [[1c4y|1c4y]], [[1c5l|1c5l]], [[1c5n|1c5n]], [[1c5o|1c5o]], [[1ca8|1ca8]], [[1d3d|1d3d]], [[1d3p|1d3p]], [[1d3q|1d3q]], [[1d3t|1d3t]], [[1d4p|1d4p]], [[1d6w|1d6w]], [[1d9i|1d9i]], [[1de7|1de7]], [[1dit|1dit]], [[1dm4|1dm4]], [[1dwb|1dwb]], [[1dwc|1dwc]], [[1dwd|1dwd]], [[1dwe|1dwe]], [[1dx5|1dx5]], [[1e0f|1e0f]], [[1eoj|1eoj]], [[1eol|1eol]], [[1fpc|1fpc]], [[1fph|1fph]], [[1hag|1hag]], [[1hah|1hah]], [[1hai|1hai]], [[1hao|1hao]], [[1hap|1hap]], [[1hbt|1hbt]], [[1hdt|1hdt]], [[1hgt|1hgt]], [[1hlt|1hlt]], [[1hut|1hut]], [[1hxe|1hxe]], [[1hxf|1hxf]], [[1ihs|1ihs]], [[1iht|1iht]], [[1lhc|1lhc]], [[1lhd|1lhd]], [[1lhe|1lhe]], [[1lhf|1lhf]], [[1lhg|1lhg]], [[1nrn|1nrn]], [[1nro|1nro]], [[1nrp|1nrp]], [[1nrq|1nrq]], [[1nrr|1nrr]], [[1nrs|1nrs]], [[1ppb|1ppb]], [[1qbv|1qbv]], [[1qhr|1qhr]], [[1qj1|1qj1]], [[1qj6|1qj6]], [[1qj7|1qj7]], [[1qur|1qur]], [[1tbz|1tbz]], [[1thp|1thp]], [[1thr|1thr]], [[1ths|1ths]], [[1tmb|1tmb]], [[1tmt|1tmt]], [[1tmu|1tmu]], [[1tom|1tom]], [[1uma|1uma]], [[1uvs|1uvs]], [[1vr1|1vr1]], [[2hgt|2hgt]], [[2hnt|2hnt]], [[2hpp|2hpp]], [[2hpq|2hpq]], [[2thf|2thf]], [[3hat|3hat]], [[3htc|3htc]], [[4htc|4htc]], [[4thn|4thn]], [[5gds|5gds]], [[7kme|7kme]], [[8kme|8kme]]</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Thrombin Thrombin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.5 3.4.21.5] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1h8d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h8d OCA], [http://pdbe.org/1h8d PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1h8d RCSB], [http://www.ebi.ac.uk/pdbsum/1h8d PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1h8d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h8d OCA], [http://pdbe.org/1h8d PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1h8d RCSB], [http://www.ebi.ac.uk/pdbsum/1h8d PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1h8d ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 17: / Line 18: @@
 Check<jmol>
   <jmolCheckbox>
-    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/h8/1h8d_consurf.spt"</scriptWhenChecked>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/h8/1h8d_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
@@ Line 32: / Line 33: @@
 </div>
 <div class="pdbe-citations 1h8d" style="background-color:#fffaf0;"></div>
-==See Also==
-*[[Hirudin|Hirudin]]
-*[[Thrombin|Thrombin]]
 == References ==
 <references/>

1h8d

From Proteopedia

Revision as of 09:17, 10 January 2018

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

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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