1sr5 is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
[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] [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.[36][37][38][39][40][41][42][43][44][45][46][47] 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.[48] 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.[49]
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.[50] [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.[51]
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
Antithrombin, the principal physiological inhibitor of the blood coagulation proteinase thrombin, requires heparin as a cofactor. We report the crystal structure of the rate-determining encounter complex formed between antithrombin, anhydrothrombin and an optimal synthetic 16-mer oligosaccharide. The antithrombin reactive center loop projects from the serpin body and adopts a canonical conformation that makes extensive backbone and side chain contacts from P5 to P6' with thrombin's restrictive specificity pockets, including residues in the 60-loop. These contacts rationalize many earlier mutagenesis studies on thrombin specificity. The 16-mer oligosaccharide is just long enough to form the predicted bridge between the high-affinity pentasaccharide-binding site on antithrombin and the highly basic exosite 2 on thrombin, validating the design strategy for this synthetic heparin. The protein-protein and protein-oligosaccharide interactions together explain the basis for heparin activation of antithrombin as a thrombin inhibitor.
The ternary complex of antithrombin-anhydrothrombin-heparin reveals the basis of inhibitor specificity.,Dementiev A, Petitou M, Herbert JM, Gettins PG Nat Struct Mol Biol. 2004 Sep;11(9):863-7. Epub 2004 Aug 15. PMID:15311268[52]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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↑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
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↑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
↑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
↑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
↑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
↑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
↑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
↑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
↑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
↑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
↑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
↑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
↑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
↑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
↑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:https://dx.doi.org/10.1006/geno.1993.1184
↑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
↑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
↑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
↑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
↑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:https://dx.doi.org/10.1172/JCI117589
↑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
↑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
↑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
↑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
↑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
↑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
↑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
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↑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
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↑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
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↑Dementiev A, Petitou M, Herbert JM, Gettins PG. The ternary complex of antithrombin-anhydrothrombin-heparin reveals the basis of inhibitor specificity. Nat Struct Mol Biol. 2004 Sep;11(9):863-7. Epub 2004 Aug 15. PMID:15311268 doi:10.1038/nsmb810
