2znh 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.
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.
Publication Abstract from PubMed
Repeating intermolecular protein association by means of beta-sheet expansion is the mechanism underlying a multitude of diseases including Alzheimer's, Huntington's and Parkinson's and the prion encephalopathies. A family of proteins, known as the serpins, also forms large stable multimers by ordered beta-sheet linkages leading to intracellular accretion and disease. These 'serpinopathies' include early-onset dementia caused by mutations in neuroserpin, liver cirrhosis and emphysema caused by mutations in alpha(1)-antitrypsin (alpha(1)AT), and thrombosis caused by mutations in antithrombin. Serpin structure and function are quite well understood, and the family has therefore become a model system for understanding the beta-sheet expansion disorders collectively known as the conformational diseases. To develop strategies to prevent and reverse these disorders, it is necessary to determine the structural basis of the intermolecular linkage and of the pathogenic monomeric state. Here we report the crystallographic structure of a stable serpin dimer which reveals a domain swap of more than 50 residues, including two long antiparallel beta-strands inserting in the centre of the principal beta-sheet of the neighbouring monomer. This structure explains the extreme stability of serpin polymers, the molecular basis of their rapid propagation, and provides critical new insights into the structural changes which initiate irreversible beta-sheet expansion.
Crystal structure of a stable dimer reveals the molecular basis of serpin polymerization.,Yamasaki M, Li W, Johnson DJ, Huntington JA Nature. 2008 Oct 30;455(7217):1255-8. Epub 2008 Oct 15. PMID:18923394[37]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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↑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
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↑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
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↑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
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↑Yamasaki M, Li W, Johnson DJ, Huntington JA. Crystal structure of a stable dimer reveals the molecular basis of serpin polymerization. Nature. 2008 Oct 30;455(7217):1255-8. Epub 2008 Oct 15. PMID:18923394 doi:10.1038/nature07394
