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==Factor XIa in complex with the inhibitor (2S)-6-amino-N-{(1S)-1-[4-(3-amino-2H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl]-2-phenylethyl}-2-ethylhexanamide==
==Factor XIa in complex with the inhibitor (2S)-6-amino-N-{(1S)-1-[4-(3-amino-2H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl]-2-phenylethyl}-2-ethylhexanamide==
<StructureSection load='4ty7' size='340' side='right' caption='[[4ty7]], [[Resolution|resolution]] 2.09&Aring;' scene=''>
<StructureSection load='4ty7' size='340' side='right' caption='[[4ty7]], [[Resolution|resolution]] 2.09&Aring;' scene=''>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=39F:(2S)-6-AMINO-N-{(1S)-1-[4-(3-AMINO-2H-INDAZOL-6-YL)-5-CHLORO-1H-IMIDAZOL-2-YL]-2-PHENYLETHYL}-2-ETHYLHEXANAMIDE'>39F</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=39F:(2S)-6-AMINO-N-{(1S)-1-[4-(3-AMINO-2H-INDAZOL-6-YL)-5-CHLORO-1H-IMIDAZOL-2-YL]-2-PHENYLETHYL}-2-ETHYLHEXANAMIDE'>39F</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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'>[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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ty7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ty7 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ty7 RCSB], [http://www.ebi.ac.uk/pdbsum/4ty7 PDBsum]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ty7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ty7 OCA], [http://pdbe.org/4ty7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ty7 RCSB], [http://www.ebi.ac.uk/pdbsum/4ty7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ty7 ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
Line 19: Line 20:
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
</div>
<div class="pdbe-citations 4ty7" style="background-color:#fffaf0;"></div>
==See Also==
*[[Factor XIa|Factor XIa]]
== References ==
== References ==
<references/>
<references/>

Revision as of 04:16, 19 January 2017

Factor XIa in complex with the inhibitor (2S)-6-amino-N-{(1S)-1-[4-(3-amino-2H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl]-2-phenylethyl}-2-ethylhexanamideFactor XIa in complex with the inhibitor (2S)-6-amino-N-{(1S)-1-[4-(3-amino-2H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl]-2-phenylethyl}-2-ethylhexanamide

Structural highlights

4ty7 is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:, ,
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.

Publication Abstract from PubMed

Novel inhibitors of FXIa containing an (S)-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine core have been optimized to provide compound 16b, a potent, reversible inhibitor of FXIa (Ki = 0.3 nM) having in vivo antithrombotic efficacy in the rabbit AV-shunt thrombosis model (ID50 = 0.6 mg/kg + 1 mg kg-1 h-1). Initial analog selection was informed by molecular modeling using compounds 11a and 11h overlaid onto the X-ray crystal structure of tetrahydroquinoline 3 complexed to FXIa. Further optimization was achieved by specific modifications derived from careful analysis of the X-ray crystal structure of the FXIa/11h complex. Compound 16b was well tolerated and enabled extensive pharmacologic evaluation of the FXIa mechanism up to the ID90 for thrombus inhibition.

Phenylimidazoles as Potent and Selective Inhibitors of Coagulation Factor XIa with in Vivo Antithrombotic Activity.,Hangeland JJ, Friends TJ, Rossi KA, Smallheer JM, Wang C, Sun Z, Corte JR, Fang T, Wong PC, Rendina AR, Barbera FA, Bozarth JM, Luettgen JM, Watson CA, Zhang G, Wei A, Ramamurthy V, Morin PE, Bisacchi GS, Subramaniam S, Arunachalam P, Mathur A, Seiffert DA, Wexler RR, Quan ML J Med Chem. 2014 Dec 2. PMID:25405503[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. ↑ Hangeland JJ, Friends TJ, Rossi KA, Smallheer JM, Wang C, Sun Z, Corte JR, Fang T, Wong PC, Rendina AR, Barbera FA, Bozarth JM, Luettgen JM, Watson CA, Zhang G, Wei A, Ramamurthy V, Morin PE, Bisacchi GS, Subramaniam S, Arunachalam P, Mathur A, Seiffert DA, Wexler RR, Quan ML. Phenylimidazoles as Potent and Selective Inhibitors of Coagulation Factor XIa with in Vivo Antithrombotic Activity. J Med Chem. 2014 Dec 2. PMID:25405503 doi:http://dx.doi.org/10.1021/jm5010607

4ty7, resolution 2.09Å

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