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<StructureSection load='1ath' size='340' side='right'caption='[[1ath]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
<StructureSection load='1ath' size='340' side='right'caption='[[1ath]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[1ath]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1ATH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1ATH FirstGlance]. <br>
<table><tr><td colspan='2'>[[1ath]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1ATH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1ATH FirstGlance]. <br>
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1ath FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ath OCA], [https://pdbe.org/1ath PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1ath RCSB], [https://www.ebi.ac.uk/pdbsum/1ath PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1ath ProSAT]</span></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.2&#8491;</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1ath FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ath OCA], [https://pdbe.org/1ath PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1ath RCSB], [https://www.ebi.ac.uk/pdbsum/1ath PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1ath ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
[[https://www.uniprot.org/uniprot/ANT3_HUMAN ANT3_HUMAN]] Defects in SERPINC1 are the cause of antithrombin III deficiency (AT3D) [MIM:[https://omim.org/entry/613118 613118]]. AT3D is an important risk factor for hereditary thrombophilia, a hemostatic disorder characterized by a tendency to recurrent thrombosis. AT3D is classified into 4 types. Type I: characterized by a 50% decrease in antigenic and functional levels. Type II: has defects affecting the thrombin-binding domain. Type III: alteration of the heparin-binding domain. Plasma AT-III antigen levels are normal in type II and III. Type IV: consists of miscellaneous group of unclassifiable mutations.<ref>PMID:7734359</ref> [:]<ref>PMID:3191114</ref> <ref>PMID:9031473</ref> <ref>PMID:6582486</ref> <ref>PMID:3080419</ref> <ref>PMID:3805013</ref> <ref>PMID:3179438</ref> <ref>PMID:3162733</ref> <ref>PMID:2781509</ref> <ref>PMID:2365065</ref> <ref>PMID:2229057</ref> <ref>PMID:2013320</ref> <ref>PMID:1906811</ref> <ref>PMID:1555650</ref> <ref>PMID:1547341</ref> <ref>PMID:8443391</ref> <ref>PMID:8486379</ref> <ref>PMID:7981186</ref> <ref>PMID:7959685</ref> <ref>PMID:8274732</ref> <ref>PMID:7994035</ref> <ref>PMID:7989582</ref> [:]<ref>PMID:7878627</ref> <ref>PMID:7832187</ref> <ref>PMID:9157604</ref> <ref>PMID:9845533</ref> <ref>PMID:9759613</ref> <ref>PMID:10997988</ref> <ref>PMID:11794707</ref> <ref>PMID:11713457</ref> <ref>PMID:12353073</ref> <ref>PMID:12595305</ref> <ref>PMID:12894857</ref> <ref>PMID:15164384</ref> <ref>PMID:16908819</ref>
[https://www.uniprot.org/uniprot/ANT3_HUMAN ANT3_HUMAN] Defects in SERPINC1 are the cause of antithrombin III deficiency (AT3D) [MIM:[https://omim.org/entry/613118 613118]. AT3D is an important risk factor for hereditary thrombophilia, a hemostatic disorder characterized by a tendency to recurrent thrombosis. AT3D is classified into 4 types. Type I: characterized by a 50% decrease in antigenic and functional levels. Type II: has defects affecting the thrombin-binding domain. Type III: alteration of the heparin-binding domain. Plasma AT-III antigen levels are normal in type II and III. Type IV: consists of miscellaneous group of unclassifiable mutations.<ref>PMID:7734359</ref> [:]<ref>PMID:3191114</ref> <ref>PMID:9031473</ref> <ref>PMID:6582486</ref> <ref>PMID:3080419</ref> <ref>PMID:3805013</ref> <ref>PMID:3179438</ref> <ref>PMID:3162733</ref> <ref>PMID:2781509</ref> <ref>PMID:2365065</ref> <ref>PMID:2229057</ref> <ref>PMID:2013320</ref> <ref>PMID:1906811</ref> <ref>PMID:1555650</ref> <ref>PMID:1547341</ref> <ref>PMID:8443391</ref> <ref>PMID:8486379</ref> <ref>PMID:7981186</ref> <ref>PMID:7959685</ref> <ref>PMID:8274732</ref> <ref>PMID:7994035</ref> <ref>PMID:7989582</ref> [:]<ref>PMID:7878627</ref> <ref>PMID:7832187</ref> <ref>PMID:9157604</ref> <ref>PMID:9845533</ref> <ref>PMID:9759613</ref> <ref>PMID:10997988</ref> <ref>PMID:11794707</ref> <ref>PMID:11713457</ref> <ref>PMID:12353073</ref> <ref>PMID:12595305</ref> <ref>PMID:12894857</ref> <ref>PMID:15164384</ref> <ref>PMID:16908819</ref>  
== Function ==
== Function ==
[[https://www.uniprot.org/uniprot/ANT3_HUMAN ANT3_HUMAN]] Most important serine protease inhibitor in plasma that regulates the blood coagulation cascade. AT-III inhibits thrombin, matriptase-3/TMPRSS7, as well as factors IXa, Xa and XIa. Its inhibitory activity is greatly enhanced in the presence of heparin.<ref>PMID:15853774</ref>
[https://www.uniprot.org/uniprot/ANT3_HUMAN ANT3_HUMAN] Most important serine protease inhibitor in plasma that regulates the blood coagulation cascade. AT-III inhibits thrombin, matriptase-3/TMPRSS7, as well as factors IXa, Xa and XIa. Its inhibitory activity is greatly enhanced in the presence of heparin.<ref>PMID:15853774</ref>  
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1ath ConSurf].
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1ath ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Antithrombin is a member of the serine proteinase inhibitor (serpin) family which contain a flexible reactive site loop that interacts with, and is cleaved by the target proteinase. In cleaved and latent serpins, the reactive site loop is inserted into a large central beta-sheet in the same molecule, whereas in ovalbumin, a nonfunctional serpin, the reactive site loop is completely exposed and in an alpha-helical conformation. However, in neither conformation can the reactive site loop bind to target proteinases. Here we report the structure of an intact and cleaved human antithrombin complex. The intact reactive site loop is in a novel conformation that seems well suited for interaction with proteinases such as thrombin and blood coagulation factor Xa.
The intact and cleaved human antithrombin III complex as a model for serpin-proteinase interactions.,Schreuder HA, de Boer B, Dijkema R, Mulders J, Theunissen HJ, Grootenhuis PD, Hol WG Nat Struct Biol. 1994 Jan;1(1):48-54. PMID:7656006<ref>PMID:7656006</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 1ath" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Hol, W G.J]]
[[Category: Hol WGJ]]
[[Category: Schreuder, H A]]
[[Category: Schreuder HA]]
[[Category: Human antithrombin-iii]]

Revision as of 18:28, 13 March 2024

THE INTACT AND CLEAVED HUMAN ANTITHROMBIN III COMPLEX AS A MODEL FOR SERPIN-PROTEINASE INTERACTIONSTHE INTACT AND CLEAVED HUMAN ANTITHROMBIN III COMPLEX AS A MODEL FOR SERPIN-PROTEINASE INTERACTIONS

Structural highlights

1ath is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.2Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ANT3_HUMAN Defects in SERPINC1 are the cause of antithrombin III deficiency (AT3D) [MIM:613118. AT3D is an important risk factor for hereditary thrombophilia, a hemostatic disorder characterized by a tendency to recurrent thrombosis. AT3D is classified into 4 types. Type I: characterized by a 50% decrease in antigenic and functional levels. Type II: has defects affecting the thrombin-binding domain. Type III: alteration of the heparin-binding domain. Plasma AT-III antigen levels are normal in type II and III. Type IV: consists of miscellaneous group of unclassifiable mutations.[1] [:][2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [:][23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35]

Function

ANT3_HUMAN Most important serine protease inhibitor in plasma that regulates the blood coagulation cascade. AT-III inhibits thrombin, matriptase-3/TMPRSS7, as well as factors IXa, Xa and XIa. Its inhibitory activity is greatly enhanced in the presence of heparin.[36]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

References

  1. ↑ Lindo VS, Kakkar VV, Learmonth M, Melissari E, Zappacosta F, Panico M, Morris HR. Antithrombin-TRI (Ala382 to Thr) causing severe thromboembolic tendency undergoes the S-to-R transition and is associated with a plasma-inactive high-molecular-weight complex of aggregated antithrombin. Br J Haematol. 1995 Mar;89(3):589-601. PMID:7734359
  2. ↑ Bock SC, Marrinan JA, Radziejewska E. Antithrombin III Utah: proline-407 to leucine mutation in a highly conserved region near the inhibitor reactive site. Biochemistry. 1988 Aug 9;27(16):6171-8. PMID:3191114
  3. ↑ Lane DA, Bayston T, Olds RJ, Fitches AC, Cooper DN, Millar DS, Jochmans K, Perry DJ, Okajima K, Thein SL, Emmerich J. Antithrombin mutation database: 2nd (1997) update. For the Plasma Coagulation Inhibitors Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost. 1997 Jan;77(1):197-211. PMID:9031473
  4. ↑ Koide T, Odani S, Takahashi K, Ono T, Sakuragawa N. Antithrombin III Toyama: replacement of arginine-47 by cysteine in hereditary abnormal antithrombin III that lacks heparin-binding ability. Proc Natl Acad Sci U S A. 1984 Jan;81(2):289-93. PMID:6582486
  5. ↑ Chang JY, Tran TH. Antithrombin III Basel. Identification of a Pro-Leu substitution in a hereditary abnormal antithrombin with impaired heparin cofactor activity. J Biol Chem. 1986 Jan 25;261(3):1174-6. PMID:3080419
  6. ↑ Stephens AW, Thalley BS, Hirs CH. Antithrombin-III Denver, a reactive site variant. J Biol Chem. 1987 Jan 25;262(3):1044-8. PMID:3805013
  7. ↑ Devraj-Kizuk R, Chui DH, Prochownik EV, Carter CJ, Ofosu FA, Blajchman MA. Antithrombin-III-Hamilton: a gene with a point mutation (guanine to adenine) in codon 382 causing impaired serine protease reactivity. Blood. 1988 Nov;72(5):1518-23. PMID:3179438
  8. ↑ Erdjument H, Lane DA, Panico M, Di Marzo V, Morris HR. Single amino acid substitutions in the reactive site of antithrombin leading to thrombosis. Congenital substitution of arginine 393 to cysteine in antithrombin Northwick Park and to histidine in antithrombin Glasgow. J Biol Chem. 1988 Apr 25;263(12):5589-93. PMID:3162733
  9. ↑ Erdjument H, Lane DA, Panico M, Di Marzo V, Morris HR, Bauer K, Rosenberg RD. Antithrombin Chicago, amino acid substitution of arginine 393 to histidine. Thromb Res. 1989 Jun 15;54(6):613-9. PMID:2781509
  10. ↑ Borg JY, Brennan SO, Carrell RW, George P, Perry DJ, Shaw J. Antithrombin Rouen-IV 24 Arg----Cys. The amino-terminal contribution to heparin binding. FEBS Lett. 1990 Jun 18;266(1-2):163-6. PMID:2365065
  11. ↑ Gandrille S, Aiach M, Lane DA, Vidaud D, Molho-Sabatier P, Caso R, de Moerloose P, Fiessinger JN, Clauser E. Important role of arginine 129 in heparin-binding site of antithrombin III. Identification of a novel mutation arginine 129 to glutamine. J Biol Chem. 1990 Nov 5;265(31):18997-9001. PMID:2229057
  12. ↑ Austin RC, Rachubinski RA, Blajchman MA. Site-directed mutagenesis of alanine-382 of human antithrombin III. FEBS Lett. 1991 Mar 25;280(2):254-8. PMID:2013320
  13. ↑ Perry DJ, Daly M, Harper PL, Tait RC, Price J, Walker ID, Carrell RW. Antithrombin Cambridge II, 384 Ala to Ser. Further evidence of the role of the reactive centre loop in the inhibitory function of the serpins. FEBS Lett. 1991 Jul 22;285(2):248-50. PMID:1906811
  14. ↑ Olds RJ, Lane DA, Boisclair M, Sas G, Bock SC, Thein SL. Antithrombin Budapest 3. An antithrombin variant with reduced heparin affinity resulting from the substitution L99F. FEBS Lett. 1992 Apr 6;300(3):241-6. PMID:1555650
  15. ↑ Blajchman MA, Fernandez-Rachubinski F, Sheffield WP, Austin RC, Schulman S. Antithrombin-III-Stockholm: a codon 392 (Gly----Asp) mutation with normal heparin binding and impaired serine protease reactivity. Blood. 1992 Mar 15;79(6):1428-34. PMID:1547341
  16. ↑ Okajima K, Abe H, Maeda S, Motomura M, Tsujihata M, Nagataki S, Okabe H, Takatsuki K. Antithrombin III Nagasaki (Ser116-Pro): a heterozygous variant with defective heparin binding associated with thrombosis. Blood. 1993 Mar 1;81(5):1300-5. PMID:8443391
  17. ↑ Olds RJ, Lane DA, Beresford CH, Abildgaard U, Hughes PM, Thein SL. A recurrent deletion in the antithrombin gene, AT106-108(-6 bp), identified by DNA heteroduplex detection. Genomics. 1993 Apr;16(1):298-9. PMID:8486379 doi:http://dx.doi.org/10.1006/geno.1993.1184
  18. ↑ Emmerich J, Vidaud D, Alhenc-Gelas M, Chadeuf G, Gouault-Heilmann M, Aillaud MF, Aiach M. Three novel mutations of antithrombin inducing high-molecular-mass compounds. Arterioscler Thromb. 1994 Dec;14(12):1958-65. PMID:7981186
  19. ↑ Millar DS, Wacey AI, Ribando J, Melissari E, Laursen B, Woods P, Kakkar VV, Cooper DN. Three novel missense mutations in the antithrombin III (AT3) gene causing recurrent venous thrombosis. Hum Genet. 1994 Nov;94(5):509-12. PMID:7959685
  20. ↑ Jochmans K, Lissens W, Vervoort R, Peeters S, De Waele M, Liebaers I. Antithrombin-Gly 424 Arg: a novel point mutation responsible for type 1 antithrombin deficiency and neonatal thrombosis. Blood. 1994 Jan 1;83(1):146-51. PMID:8274732
  21. ↑ van Boven HH, Olds RJ, Thein SL, Reitsma PH, Lane DA, Briet E, Vandenbroucke JP, Rosendaal FR. Hereditary antithrombin deficiency: heterogeneity of the molecular basis and mortality in Dutch families. Blood. 1994 Dec 15;84(12):4209-13. PMID:7994035
  22. ↑ Bruce D, Perry DJ, Borg JY, Carrell RW, Wardell MR. Thromboembolic disease due to thermolabile conformational changes of antithrombin Rouen-VI (187 Asn-->Asp) J Clin Invest. 1994 Dec;94(6):2265-74. PMID:7989582 doi:http://dx.doi.org/10.1172/JCI117589
  23. ↑ Emmerich J, Chadeuf G, Alhenc-Gelas M, Gouault-Heilman M, Toulon P, Fiessinger JN, Aiach M. Molecular basis of antithrombin type I deficiency: the first large in-frame deletion and two novel mutations in exon 6. Thromb Haemost. 1994 Oct;72(4):534-9. PMID:7878627
  24. ↑ Okajima K, Abe H, Wagatsuma M, Okabe H, Takatsuki K. Antithrombin III Kumamoto II; a single mutation at Arg393-His increased the affinity of antithrombin III for heparin. Am J Hematol. 1995 Jan;48(1):12-8. PMID:7832187
  25. ↑ Ozawa T, Takikawa Y, Niiya K, Fujiwara T, Suzuki K, Sato S, Sakuragawa N. Antithrombin Morioka (Cys 95-Arg): a novel missense mutation causing type I antithrombin deficiency. Thromb Haemost. 1997 Feb;77(2):403. PMID:9157604
  26. ↑ Fitches AC, Appleby R, Lane DA, De Stefano V, Leone G, Olds RJ. Impaired cotranslational processing as a mechanism for type I antithrombin deficiency. Blood. 1998 Dec 15;92(12):4671-6. PMID:9845533
  27. ↑ Jochmans K, Lissens W, Seneca S, Capel P, Chatelain B, Meeus P, Osselaer JC, Peerlinck K, Seghers J, Slacmeulder M, Stibbe J, van de Loo J, Vermylen J, Liebaers I, De Waele M. The molecular basis of antithrombin deficiency in Belgian and Dutch families. Thromb Haemost. 1998 Sep;80(3):376-81. PMID:9759613
  28. ↑ Picard V, Bura A, Emmerich J, Alhenc-Gelas M, Biron C, Houbouyan-Reveillard LL, Molho P, Labatide-Alanore A, Sie P, Toulon P, Verdy E, Aiach M. Molecular bases of antithrombin deficiency in French families: identification of seven novel mutations in the antithrombin gene. Br J Haematol. 2000 Sep;110(3):731-4. PMID:10997988
  29. ↑ Niiya K, Kiguchi T, Dansako H, Fujimura K, Fujimoto T, Iijima K, Tanimoto M, Harada M. Two novel gene mutations in type I antithrombin deficiency. Int J Hematol. 2001 Dec;74(4):469-72. PMID:11794707
  30. ↑ Baud O, Picard V, Durand P, Duchemin J, Proulle V, Alhenc-Gelas M, Devictor D, Dreyfus M. Intracerebral hemorrhage associated with a novel antithrombin gene mutation in a neonate. J Pediatr. 2001 Nov;139(5):741-3. PMID:11713457 doi:10.1067/mpd.2001.118191
  31. ↑ Mushunje A, Zhou A, Huntington JA, Conard J, Carrell RW. Antithrombin 'DREUX' (Lys 114Glu): a variant with complete loss of heparin affinity. Thromb Haemost. 2002 Sep;88(3):436-43. PMID:12353073 doi:10.1267/THRO88030436
  32. ↑ Picard V, Dautzenberg MD, Villoutreix BO, Orliaguet G, Alhenc-Gelas M, Aiach M. Antithrombin Phe229Leu: a new homozygous variant leading to spontaneous antithrombin polymerization in vivo associated with severe childhood thrombosis. Blood. 2003 Aug 1;102(3):919-25. Epub 2003 Feb 20. PMID:12595305 doi:10.1182/blood-2002-11-3391
  33. ↑ Nagaizumi K, Inaba H, Amano K, Suzuki M, Arai M, Fukutake K. Five novel and four recurrent point mutations in the antithrombin gene causing venous thrombosis. Int J Hematol. 2003 Jul;78(1):79-83. PMID:12894857
  34. ↑ David D, Ribeiro S, Ferrao L, Gago T, Crespo F. Molecular basis of inherited antithrombin deficiency in Portuguese families: identification of genetic alterations and screening for additional thrombotic risk factors. Am J Hematol. 2004 Jun;76(2):163-71. PMID:15164384 doi:10.1002/ajh.20067
  35. ↑ Kuhli C, Jochmans K, Scharrer I, Luchtenberg M, Hattenbach LO. Retinal vein occlusion associated with antithrombin deficiency secondary to a novel G9840C missense mutation. Arch Ophthalmol. 2006 Aug;124(8):1165-9. PMID:16908819 doi:10.1001/archopht.124.8.1165
  36. ↑ Szabo R, Netzel-Arnett S, Hobson JP, Antalis TM, Bugge TH. Matriptase-3 is a novel phylogenetically preserved membrane-anchored serine protease with broad serpin reactivity. Biochem J. 2005 Aug 15;390(Pt 1):231-42. PMID:15853774 doi:BJ20050299

1ath, resolution 3.20Å

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