2ra0 is a 2 chain structure with sequence from Human. 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
We have developed a novel series of potent and selective factor Xa inhibitors that employ a key 7-fluoroindazolyl moiety. The 7-fluoro group on the indazole scaffold replaces the carbonyl group of an amide that is found in previously reported factor Xa inhibitors. The structure of a factor Xa cocrystal containing 7-fluoroindazole 51a showed the 7-fluoro atom hydrogen-bonding with the N-H of Gly216 (2.9 A) in the peptide backbone. Thus, the 7-fluoroindazolyl moiety not only occupied the same space as the carbonyl group of an amide found in prior factor Xa inhibitors but also maintained a hydrogen bond interaction with the protein's beta-sheet domain. The structure-activity relationship for this series was consistent with this finding, as the factor Xa inhibitory potencies were about 60-fold greater (DeltaDelta G approximately 2.4 kcal/mol) for the 7-fluoroindazoles 25a and 25c versus the corresponding indazoles 25b and 25d. Highly convergent synthesis of these factor Xa inhibitors is also described.
7-fluoroindazoles as potent and selective inhibitors of factor Xa.,Lee YK, Parks DJ, Lu T, Thieu TV, Markotan T, Pan W, McComsey DF, Milkiewicz KL, Crysler CS, Ninan N, Abad MC, Giardino EC, Maryanoff BE, Damiano BP, Player MR J Med Chem. 2008 Jan 24;51(2):282-97. Epub 2007 Dec 27. PMID:18159923[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
↑Lee YK, Parks DJ, Lu T, Thieu TV, Markotan T, Pan W, McComsey DF, Milkiewicz KL, Crysler CS, Ninan N, Abad MC, Giardino EC, Maryanoff BE, Damiano BP, Player MR. 7-fluoroindazoles as potent and selective inhibitors of factor Xa. J Med Chem. 2008 Jan 24;51(2):282-97. Epub 2007 Dec 27. PMID:18159923 doi:10.1021/jm701217r
