3kl6 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.
[FA10_HUMAN] Defects in F10 are the cause of factor X deficiency (FA10D) [MIM:227600]. A hemorrhagic disease with variable presentation. Affected individuals can manifest prolonged nasal and mucosal hemorrhage, menorrhagia, hematuria, and occasionally hemarthrosis. Some patients do not have clinical bleeding diathesis.[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]
Function
[FA10_HUMAN] Factor Xa is a vitamin K-dependent glycoprotein that converts prothrombin to thrombin in the presence of factor Va, calcium and phospholipid during blood clotting.
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
Coagulation enzyme factor Xa (FXa) is a particularly promising target for the development of new anticoagulant agents. We previously reported the imidazo[1,5-c]imidazol-3-one derivative 1 as a potent and orally active FXa inhibitor. However, it was found that 1 predominantly undergoes hydrolysis upon incubation with human liver microsomes, and the human specific metabolic pathway made it difficult to predict the human pharmacokinetics. To address this issue, our synthetic efforts were focused on modification of the imidazo[1,5-c]imidazol-3-one moiety of the active metabolite 3a, derived from 1, which resulted in the discovery of the tetrahydropyrimidin-2(1H)-one derivative 5k as a highly potent and selective FXa inhibitor. Compound 5k showed no detectable amide bond cleavage in human liver microsomes, exhibited a good pharmacokinetic profile in monkeys, and had a potent antithrombotic efficacy in a rabbit model without prolongation of bleeding time. Compound 5k is currently under clinical development with the code name TAK-442.
Discovery of a tetrahydropyrimidin-2(1H)-one derivative (TAK-442) as a potent, selective, and orally active factor Xa inhibitor.,Fujimoto T, Imaeda Y, Konishi N, Hiroe K, Kawamura M, Textor GP, Aertgeerts K, Kubo K J Med Chem. 2010 May 13;53(9):3517-31. PMID:20355714[18]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
↑Reddy SV, Zhou ZQ, Rao KJ, Scott JP, Watzke H, High KA, Jagadeeswaran P. Molecular characterization of human factor XSan Antonio. Blood. 1989 Oct;74(5):1486-90. PMID:2790181
↑Watzke HH, Lechner K, Roberts HR, Reddy SV, Welsch DJ, Friedman P, Mahr G, Jagadeeswaran P, Monroe DM, High KA. Molecular defect (Gla+14----Lys) and its functional consequences in a hereditary factor X deficiency (factor X "Vorarlberg"). J Biol Chem. 1990 Jul 15;265(20):11982-9. PMID:1973167
↑James HL, Girolami A, Fair DS. Molecular defect in coagulation factor XFriuli results from a substitution of serine for proline at position 343. Blood. 1991 Jan 15;77(2):317-23. PMID:1985698
↑Marchetti G, Castaman G, Pinotti M, Lunghi B, Di Iasio MG, Ruggieri M, Rodeghiero F, Bernardi F. Molecular bases of CRM+ factor X deficiency: a frequent mutation (Ser334Pro) in the catalytic domain and a substitution (Glu102Lys) in the second EGF-like domain. Br J Haematol. 1995 Aug;90(4):910-5. PMID:7669671
↑Bezeaud A, Miyata T, Helley D, Zeng YZ, Kato H, Aillaud MF, Juhan-Vague I, Guillin MC. Functional consequences of the Ser334-->Pro mutation in a human factor X variant (factor XMarseille). Eur J Biochem. 1995 Nov 15;234(1):140-7. PMID:8529633
↑Kim DJ, Thompson AR, James HL. Factor XKetchikan: a variant molecule in which Gly replaces a Gla residue at position 14 in the light chain. Hum Genet. 1995 Feb;95(2):212-4. PMID:7860069
↑Messier TL, Wong CY, Bovill EG, Long GL, Church WR. Factor X Stockton: a mild bleeding diathesis associated with an active site mutation in factor X. Blood Coagul Fibrinolysis. 1996 Jan;7(1):5-14. PMID:8845463
↑Rudolph AE, Mullane MP, Porche-Sorbet R, Tsuda S, Miletich JP. Factor XSt. Louis II. Identification of a glycine substitution at residue 7 and characterization of the recombinant protein. J Biol Chem. 1996 Nov 8;271(45):28601-6. PMID:8910490
↑Zama T, Murata M, Watanabe R, Yokoyama K, Moriki T, Ambo H, Murakami H, Kikuchi M, Ikeda Y. A family with hereditary factor X deficiency with a point mutation Gla32 to Gln in the Gla domain (factor X Tokyo). Br J Haematol. 1999 Sep;106(3):809-11. PMID:10468877
↑Millar DS, Elliston L, Deex P, Krawczak M, Wacey AI, Reynaud J, Nieuwenhuis HK, Bolton-Maggs P, Mannucci PM, Reverter JC, Cachia P, Pasi KJ, Layton DM, Cooper DN. Molecular analysis of the genotype-phenotype relationship in factor X deficiency. Hum Genet. 2000 Feb;106(2):249-57. PMID:10746568
↑Forberg E, Huhmann I, Jimenez-Boj E, Watzke HH. The impact of Glu102Lys on the factor X function in a patient with a doubly homozygous factor X deficiency (Gla14Lys and Glu102Lys). Thromb Haemost. 2000 Feb;83(2):234-8. PMID:10739379
↑Simioni P, Vianello F, Kalafatis M, Barzon L, Ladogana S, Paolucci P, Carotenuto M, Dal Bello F, Palu G, Girolami A. A dysfunctional factor X (factor X San Giovanni Rotondo) present at homozygous and double heterozygous level: identification of a novel microdeletion (delC556) and missense mutation (Lys(408)-->Asn) in the factor X gene. A study of an Italian family. Thromb Res. 2001 Feb 15;101(4):219-30. PMID:11248282
↑Vianello F, Lombardi AM, Boldrin C, Luni S, Girolami A. A new factor X defect (factor X Padua 3): a compound heterozygous between true deficiency (Gly(380)-->Arg) and an abnormality (Ser(334)-->Pro). Thromb Res. 2001 Nov 15;104(4):257-64. PMID:11728527
↑Vianello F, Lombardi AM, Bello FD, Palu G, Zanon E, Girolami A. A novel type I factor X variant (factor X Cys350Phe) due to loss of a disulfide bond in the catalytic domain. Blood Coagul Fibrinolysis. 2003 Jun;14(4):401-5. PMID:12945883
↑Isshiki I, Favier R, Moriki T, Uchida T, Ishihara H, Van Dreden P, Murata M, Ikeda Y. Genetic analysis of hereditary factor X deficiency in a French patient of Sri Lankan ancestry: in vitro expression study identified Gly366Ser substitution as the molecular basis of the dysfunctional factor X. Blood Coagul Fibrinolysis. 2005 Jan;16(1):9-16. PMID:15650540
↑Al-Hilali A, Wulff K, Abdel-Razeq H, Saud KA, Al-Gaili F, Herrmann FH. Analysis of the novel factor X gene mutation Glu51Lys in two families with factor X-Riyadh anomaly. Thromb Haemost. 2007 Apr;97(4):542-5. PMID:17393015
↑Chafa O, Tagzirt M, Tapon-Bretaudiere J, Reghis A, Fischer AM, LeBonniec BF. Characterization of a homozygous Gly11Val mutation in the Gla domain of coagulation factor X. Thromb Res. 2009 May;124(1):144-8. doi: 10.1016/j.thromres.2008.11.018. Epub 2009, Jan 10. PMID:19135706 doi:10.1016/j.thromres.2008.11.018
↑Fujimoto T, Imaeda Y, Konishi N, Hiroe K, Kawamura M, Textor GP, Aertgeerts K, Kubo K. Discovery of a tetrahydropyrimidin-2(1H)-one derivative (TAK-442) as a potent, selective, and orally active factor Xa inhibitor. J Med Chem. 2010 May 13;53(9):3517-31. PMID:20355714 doi:10.1021/jm901699j
