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<StructureSection load='1xxd' size='340' side='right'caption='[[1xxd]], [[Resolution|resolution]] 2.91&Aring;' scene=''>
<StructureSection load='1xxd' size='340' side='right'caption='[[1xxd]], [[Resolution|resolution]] 2.91&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[1xxd]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_coli"_migula_1895 "bacillus coli" migula 1895] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XXD OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=1XXD FirstGlance]. <br>
<table><tr><td colspan='2'>[[1xxd]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/"bacillus_coli"_migula_1895 "bacillus coli" migula 1895] and [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XXD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1XXD FirstGlance]. <br>
</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1xx9|1xx9]], [[1xxf|1xxf]]</div></td></tr>
</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1xx9|1xx9]], [[1xxf|1xxf]]</div></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">F11 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), eco,eti ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=562 "Bacillus coli" Migula 1895])</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">F11 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), eco,eti ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=562 "Bacillus coli" Migula 1895])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Coagulation_factor_XIa Coagulation factor XIa], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.27 3.4.21.27] </span></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Coagulation_factor_XIa Coagulation factor XIa], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.27 3.4.21.27] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=1xxd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1xxd OCA], [http://pdbe.org/1xxd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1xxd RCSB], [http://www.ebi.ac.uk/pdbsum/1xxd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1xxd ProSAT]</span></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=1xxd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1xxd OCA], [https://pdbe.org/1xxd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1xxd RCSB], [https://www.ebi.ac.uk/pdbsum/1xxd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1xxd ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
[[http://www.uniprot.org/uniprot/FA11_HUMAN FA11_HUMAN]] Defects in F11 are the cause of factor XI deficiency (FA11D) [MIM:[http://omim.org/entry/612416 612416]]; also known as plasma thromboplastin antecedent deficiency or Rosenthal syndrome. It is a hemorrhagic disease characterized by reduced levels and activity of factor XI resulting in moderate bleeding symptoms, usually occurring after trauma or surgery. Patients usually do not present spontaneous bleeding but women can present with menorrhagia. Hemorrhages are usually moderate.<ref>PMID:2813350</ref> <ref>PMID:1547342</ref> <ref>PMID:7888672</ref> <ref>PMID:7669672</ref> <ref>PMID:9401068</ref> <ref>PMID:9787168</ref> <ref>PMID:10027710</ref> <ref>PMID:10606881</ref> <ref>PMID:11895778</ref> <ref>PMID:15026311</ref> <ref>PMID:15180874</ref> <ref>PMID:15953011</ref> <ref>PMID:16607084</ref> <ref>PMID:18005151</ref> <ref>PMID:21668437</ref> <ref>PMID:21457405</ref> <ref>PMID:22016685</ref> <ref>PMID:22322133</ref> <ref>PMID:21999818</ref> <ref>PMID:22159456</ref>   
[[https://www.uniprot.org/uniprot/FA11_HUMAN FA11_HUMAN]] Defects in F11 are the cause of factor XI deficiency (FA11D) [MIM:[https://omim.org/entry/612416 612416]]; also known as plasma thromboplastin antecedent deficiency or Rosenthal syndrome. It is a hemorrhagic disease characterized by reduced levels and activity of factor XI resulting in moderate bleeding symptoms, usually occurring after trauma or surgery. Patients usually do not present spontaneous bleeding but women can present with menorrhagia. Hemorrhages are usually moderate.<ref>PMID:2813350</ref> <ref>PMID:1547342</ref> <ref>PMID:7888672</ref> <ref>PMID:7669672</ref> <ref>PMID:9401068</ref> <ref>PMID:9787168</ref> <ref>PMID:10027710</ref> <ref>PMID:10606881</ref> <ref>PMID:11895778</ref> <ref>PMID:15026311</ref> <ref>PMID:15180874</ref> <ref>PMID:15953011</ref> <ref>PMID:16607084</ref> <ref>PMID:18005151</ref> <ref>PMID:21668437</ref> <ref>PMID:21457405</ref> <ref>PMID:22016685</ref> <ref>PMID:22322133</ref> <ref>PMID:21999818</ref> <ref>PMID:22159456</ref>   
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/FA11_HUMAN FA11_HUMAN]] Factor XI triggers the middle phase of the intrinsic pathway of blood coagulation by activating factor IX. [[http://www.uniprot.org/uniprot/ECOT_ECOLI ECOT_ECOLI]] General inhibitor of pancreatic serine proteases: inhibits chymotrypsin, trypsin, elastases, factor X, kallikrein as well as a variety of other proteases. The strength of inhibition does not appear to be correlated with a particular protease specificity.[HAMAP-Rule:MF_00706]  
[[https://www.uniprot.org/uniprot/FA11_HUMAN FA11_HUMAN]] Factor XI triggers the middle phase of the intrinsic pathway of blood coagulation by activating factor IX. [[https://www.uniprot.org/uniprot/ECOT_ECOLI ECOT_ECOLI]] General inhibitor of pancreatic serine proteases: inhibits chymotrypsin, trypsin, elastases, factor X, kallikrein as well as a variety of other proteases. The strength of inhibition does not appear to be correlated with a particular protease specificity.[HAMAP-Rule:MF_00706]  
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]

Revision as of 19:45, 20 October 2021

Crystal Structure of the FXIa Catalytic Domain in Complex with mutated EcotinCrystal Structure of the FXIa Catalytic Domain in Complex with mutated Ecotin

Structural highlights

1xxd is a 4 chain structure with sequence from "bacillus_coli"_migula_1895 "bacillus coli" migula 1895 and Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Gene:F11 (HUMAN), eco,eti ("Bacillus coli" Migula 1895)
Activity:Coagulation factor XIa, with EC number 3.4.21.27
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[FA11_HUMAN] Defects in F11 are the cause of factor XI deficiency (FA11D) [MIM:612416]; also known as plasma thromboplastin antecedent deficiency or Rosenthal syndrome. It is a hemorrhagic disease characterized by reduced levels and activity of factor XI resulting in moderate bleeding symptoms, usually occurring after trauma or surgery. Patients usually do not present spontaneous bleeding but women can present with menorrhagia. Hemorrhages are usually moderate.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20]

Function

[FA11_HUMAN] Factor XI triggers the middle phase of the intrinsic pathway of blood coagulation by activating factor IX. [ECOT_ECOLI] General inhibitor of pancreatic serine proteases: inhibits chymotrypsin, trypsin, elastases, factor X, kallikrein as well as a variety of other proteases. The strength of inhibition does not appear to be correlated with a particular protease specificity.[HAMAP-Rule:MF_00706]

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

Thrombosis can lead to life-threatening conditions such as acute myocardial infarction, pulmonary embolism, and stroke. Although commonly used anti-coagulant drugs, such as low molecular weight heparin and warfarin, are effective, they carry a significant risk of inducing severe bleeding complications, and there is a need for safer drugs. Activated Factor XI (FXIa) is a key enzyme in the amplification phase of the coagulation cascade. Anti-human FXI antibody significantly reduces thrombus growth in a baboon thrombosis model without bleeding problems (Gruber, A., and Hanson, S. R. (2003) Blood 102, 953-955). Therefore, FXIa is a potential target for anti-thrombosis therapy. To determine the structure of FXIa, we derived a recombinant catalytic domain of FXI, consisting of residues 370-607 (rhFXI370-607). Here we report the first crystal structure of rhFXI370-607 in complex with a substitution mutant of ecotin, a panserine protease protein inhibitor secreted by Escherichia coli, to 2.2 A resolution. The presence of ecotin not only assisted in the crystallization of the enzyme but also revealed unique structural features in the active site of FXIa. Subsequently, the sequence from P5 to P2' in ecotin was mutated to the FXIa substrate sequence, and the structures of the rhFXI370-607-ecotin mutant complexes were determined. These structures provide us with an understanding of substrate binding interactions of FXIa, the structural information essential for the structure-based design of FXIa-selective inhibitors.

Crystal structures of the FXIa catalytic domain in complex with ecotin mutants reveal substrate-like interactions.,Jin L, Pandey P, Babine RE, Gorga JC, Seidl KJ, Gelfand E, Weaver DT, Abdel-Meguid SS, Strickler JE J Biol Chem. 2005 Feb 11;280(6):4704-12. Epub 2004 Nov 15. PMID:15545266[21]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Asakai R, Chung DW, Ratnoff OD, Davie EW. Factor XI (plasma thromboplastin antecedent) deficiency in Ashkenazi Jews is a bleeding disorder that can result from three types of point mutations. Proc Natl Acad Sci U S A. 1989 Oct;86(20):7667-71. PMID:2813350
  2. ↑ Meijers JC, Davie EW, Chung DW. Expression of human blood coagulation factor XI: characterization of the defect in factor XI type III deficiency. Blood. 1992 Mar 15;79(6):1435-40. PMID:1547342
  3. ↑ Pugh RE, McVey JH, Tuddenham EG, Hancock JF. Six point mutations that cause factor XI deficiency. Blood. 1995 Mar 15;85(6):1509-16. PMID:7888672
  4. ↑ Imanaka Y, Lal K, Nishimura T, Bolton-Maggs PH, Tuddenham EG, McVey JH. Identification of two novel mutations in non-Jewish factor XI deficiency. Br J Haematol. 1995 Aug;90(4):916-20. PMID:7669672
  5. ↑ Wistinghausen B, Reischer A, Oddoux C, Ostrer H, Nardi M, Karpatkin M. Severe factor XI deficiency in an Arab family associated with a novel mutation in exon 11. Br J Haematol. 1997 Dec;99(3):575-7. PMID:9401068
  6. ↑ Martincic D, Zimmerman SA, Ware RE, Sun MF, Whitlock JA, Gailani D. Identification of mutations and polymorphisms in the factor XI genes of an African American family by dideoxyfingerprinting. Blood. 1998 Nov 1;92(9):3309-17. PMID:9787168
  7. ↑ Alhaq A, Mitchell M, Sethi M, Rahman S, Flynn G, Boulton P, Caeno G, Smith M, Savidge G. Identification of a novel mutation in a non-Jewish factor XI deficient kindred. Br J Haematol. 1999 Jan;104(1):44-9. PMID:10027710
  8. ↑ Mitchell M, Cutler J, Thompson S, Moore G, Jenkins Ap Rees E, Smith M, Savidge G, Alhaq A. Heterozygous factor XI deficiency associated with three novel mutations. Br J Haematol. 1999 Dec;107(4):763-5. PMID:10606881
  9. ↑ Zivelin A, Bauduer F, Ducout L, Peretz H, Rosenberg N, Yatuv R, Seligsohn U. Factor XI deficiency in French Basques is caused predominantly by an ancestral Cys38Arg mutation in the factor XI gene. Blood. 2002 Apr 1;99(7):2448-54. PMID:11895778
  10. ↑ Kravtsov DV, Wu W, Meijers JC, Sun MF, Blinder MA, Dang TP, Wang H, Gailani D. Dominant factor XI deficiency caused by mutations in the factor XI catalytic domain. Blood. 2004 Jul 1;104(1):128-34. Epub 2004 Mar 16. PMID:15026311 doi:10.1182/blood-2003-10-3530
  11. ↑ Dai L, Mitchell M, Carson P, Creagh D, Cutler J, Savidge G, Alhaq A. Severe factor XI deficiency caused by compound heterozygosity. Br J Haematol. 2004 Jun;125(6):817-8. PMID:15180874 doi:10.1111/j.1365-2141.2004.04979.x
  12. ↑ Hill M, McLeod F, Franks H, Gordon B, Dolan G. Genetic analysis in FXI deficiency: six novel mutations and the use of a polymerase chain reaction-based test to define a whole gene deletion. Br J Haematol. 2005 Jun;129(6):825-9. PMID:15953011 doi:10.1111/j.1365-2141.2005.05536.x
  13. ↑ Quelin F, Mathonnet F, Potentini-Esnault C, Trigui N, Peynet J, Bastenaire B, Guillon L, Bigel ML, Sauger A, Mazurier C, de Mazancourt P. Identification of five novel mutations in the factor XI gene (F11) of patients with factor XI deficiency. Blood Coagul Fibrinolysis. 2006 Jan;17(1):69-73. PMID:16607084 doi:10.1097/01.mbc.0000198054.50257.96
  14. ↑ Fard-Esfahani P, Lari GR, Ravanbod S, Mirkhani F, Allahyari M, Rassoulzadegan M, Ala F. Seven novel point mutations in the F11 gene in Iranian FXI-deficient patients. Haemophilia. 2008 Jan;14(1):91-5. Epub 2007 Nov 13. PMID:18005151 doi:10.1111/j.1365-2516.2007.01593.x
  15. ↑ Kim J, Song J, Lyu CJ, Kim YR, Oh SH, Choi YC, Yoo JH, Choi JR, Kim H, Lee KA. Population-specific spectrum of the F11 mutations in Koreans: evidence for a founder effect. Clin Genet. 2012 Aug;82(2):180-6. doi: 10.1111/j.1399-0004.2011.01732.x. Epub, 2011 Jun 30. PMID:21668437 doi:10.1111/j.1399-0004.2011.01732.x
  16. ↑ Dai L, Rangarajan S, Mitchell M. Three dominant-negative mutations in factor XI-deficient patients. Haemophilia. 2011 Sep;17(5):e919-22. doi: 10.1111/j.1365-2516.2011.02519.x. Epub , 2011 Apr 3. PMID:21457405 doi:10.1111/j.1365-2516.2011.02519.x
  17. ↑ Lee JH, Cho HS, Hyun MS, Kim HY, Kim HJ. A novel missense mutation Asp506Gly in Exon 13 of the F11 gene in an asymptomatic Korean woman with mild factor XI deficiency. Korean J Lab Med. 2011 Oct;31(4):290-3. doi: 10.3343/kjlm.2011.31.4.290. Epub, 2011 Oct 3. PMID:22016685 doi:10.3343/kjlm.2011.31.4.290
  18. ↑ Tirefort Y, Uhr MR, Neerman-Arbez M, de Moerloose P. Identification of a novel F11 missense mutation (Ile463Ser) in a family with congenital factor XI deficiency. Blood Coagul Fibrinolysis. 2012 Apr;23(3):251-2. doi:, 10.1097/MBC.0b013e32834ea02a. PMID:22322133 doi:10.1097/MBC.0b013e32834ea02a
  19. ↑ Girolami A, Scarparo P, Bonamigo E, Santarossa L, Cristiani A, Moro S, Lombardi AM. A cluster of factor XI-deficient patients due to a new mutation (Ile 436 Lys) in northeastern Italy. Eur J Haematol. 2012 Mar;88(3):229-36. doi: 10.1111/j.1600-0609.2011.01723.x., Epub 2011 Nov 17. PMID:21999818 doi:10.1111/j.1600-0609.2011.01723.x
  20. ↑ Gueguen P, Chauvin A, Quemener-Redon S, Pan-Petesch B, Ferec C, Abgrall JF, Le Marechal C. Revisiting the molecular epidemiology of factor XI deficiency: nine new mutations and an original large 4qTer deletion in western Brittany (France). Thromb Haemost. 2012 Jan;107(1):44-50. doi: 10.1160/TH11-06-0415. Epub 2011 Dec, 8. PMID:22159456 doi:10.1160/TH11-06-0415
  21. ↑ Jin L, Pandey P, Babine RE, Gorga JC, Seidl KJ, Gelfand E, Weaver DT, Abdel-Meguid SS, Strickler JE. Crystal structures of the FXIa catalytic domain in complex with ecotin mutants reveal substrate-like interactions. J Biol Chem. 2005 Feb 11;280(6):4704-12. Epub 2004 Nov 15. PMID:15545266 doi:10.1074/jbc.M411309200

1xxd, resolution 2.91Å

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