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{{STRUCTURE_2y5h| PDB=2y5h | SCENE= }}
==FACTOR XA - CATION INHIBITOR COMPLEX==
===FACTOR XA - CATION INHIBITOR COMPLEX===
<StructureSection load='2y5h' size='340' side='right' caption='[[2y5h]], [[Resolution|resolution]] 1.33&Aring;' scene=''>
{{ABSTRACT_PUBMED_22162109}}
== Structural highlights ==
 
<table><tr><td colspan='2'>[[2y5h]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Y5H OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2Y5H FirstGlance]. <br>
==Disease==
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=Y5H:3-[(3AS,4R,5S,8AS,8BR)-4-[2-(5-CHLOROTHIOPHEN-2-YL)-1,3-OXAZOL-4-YL]-1,3-DIOXO-4,6,7,8,8A,8B-HEXAHYDRO-3AH-PYRROLO[3,4-A]PYRROLIZIN-2-YL]PROPYL-TRIMETHYL-AZANIUM'>Y5H</scene></td></tr>
[[http://www.uniprot.org/uniprot/FA10_HUMAN FA10_HUMAN]] Defects in F10 are the cause of factor X deficiency (FA10D) [MIM:[http://omim.org/entry/227600 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.<ref>PMID:2790181</ref><ref>PMID:1973167</ref><ref>PMID:1985698</ref><ref>PMID:7669671</ref><ref>PMID:8529633</ref><ref>PMID:7860069</ref><ref>PMID:8845463</ref><ref>PMID:8910490</ref><ref>PMID:10468877</ref><ref>PMID:10746568</ref><ref>PMID:10739379</ref><ref>PMID:11248282</ref><ref>PMID:11728527</ref><ref>PMID:12945883</ref><ref>PMID:15650540</ref><ref>PMID:17393015</ref><ref>PMID:19135706</ref>  
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1wu1|1wu1]], [[2j34|2j34]], [[2bq7|2bq7]], [[2w3k|2w3k]], [[2vwo|2vwo]], [[1xka|1xka]], [[1nfw|1nfw]], [[2gd4|2gd4]], [[2vvv|2vvv]], [[2xbx|2xbx]], [[1msx|1msx]], [[1lpg|1lpg]], [[2vvu|2vvu]], [[1p0s|1p0s]], [[2g00|2g00]], [[1mq6|1mq6]], [[1xkb|1xkb]], [[1iqe|1iqe]], [[1g2m|1g2m]], [[2vh0|2vh0]], [[1nfy|1nfy]], [[2uwl|2uwl]], [[2bok|2bok]], [[1hcg|1hcg]], [[1lpz|1lpz]], [[2w3i|2w3i]], [[2jkh|2jkh]], [[1z6e|1z6e]], [[2uwp|2uwp]], [[2xc4|2xc4]], [[1g2l|1g2l]], [[1nfu|1nfu]], [[2xc0|2xc0]], [[1fax|1fax]], [[2bq6|2bq6]], [[1iqf|1iqf]], [[1nl8|1nl8]], [[1iqg|1iqg]], [[1iqh|1iqh]], [[1lqd|1lqd]], [[2uwo|2uwo]], [[1c5m|1c5m]], [[1ioe|1ioe]], [[1f0s|1f0s]], [[1f0r|1f0r]], [[2xby|2xby]], [[2xc5|2xc5]], [[1mq5|1mq5]], [[2bmg|2bmg]], [[1iqn|1iqn]], [[2xbv|2xbv]], [[2bqw|2bqw]], [[1iqm|1iqm]], [[1ezq|1ezq]], [[2vwl|2vwl]], [[2vh6|2vh6]], [[1fjs|1fjs]], [[1lpk|1lpk]], [[2j4i|2j4i]], [[1nfx|1nfx]], [[2vwn|2vwn]], [[2j94|2j94]], [[1iqj|1iqj]], [[2cji|2cji]], [[2j95|2j95]], [[2boh|2boh]], [[2j38|2j38]], [[2w26|2w26]], [[2vvc|2vvc]], [[1iqi|1iqi]], [[2vwm|2vwm]], [[1kye|1kye]], [[1iqk|1iqk]], [[2wyj|2wyj]], [[1v3x|1v3x]], [[2fzz|2fzz]], [[2j2u|2j2u]], [[2xbw|2xbw]], [[1ksn|1ksn]], [[1iql|1iql]], [[2wyg|2wyg]], [[2y5g|2y5g]], [[2y5f|2y5f]]</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_Xa Coagulation factor Xa], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.6 3.4.21.6] </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=2y5h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2y5h OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2y5h RCSB], [http://www.ebi.ac.uk/pdbsum/2y5h PDBsum]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/FA10_HUMAN FA10_HUMAN]] Defects in F10 are the cause of factor X deficiency (FA10D) [MIM:[http://omim.org/entry/227600 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.<ref>PMID:2790181</ref> <ref>PMID:1973167</ref> <ref>PMID:1985698</ref> <ref>PMID:7669671</ref> <ref>PMID:8529633</ref> <ref>PMID:7860069</ref> <ref>PMID:8845463</ref> <ref>PMID:8910490</ref> <ref>PMID:10468877</ref> <ref>PMID:10746568</ref> <ref>PMID:10739379</ref> <ref>PMID:11248282</ref> <ref>PMID:11728527</ref> <ref>PMID:12945883</ref> <ref>PMID:15650540</ref> <ref>PMID:17393015</ref> <ref>PMID:19135706</ref>
== Function ==
[[http://www.uniprot.org/uniprot/FA10_HUMAN 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.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Factor Xa, a serine protease from the blood coagulation cascade, is an ideal enzyme for molecular recognition studies, as its active site is highly shape-persistent and features distinct, concave sub-pockets. We developed a family of non-peptidic, small-molecule inhibitors with a central tricyclic core orienting a neutral heterocyclic substituent into the S1 pocket and a quaternary ammonium ion into the aromatic box in the S4 pocket. The substituents were systematically varied to investigate cation-pi interactions in the S4 pocket, optimal heterocyclic stacking on the flat peptide walls lining the S1 pocket, and potential water replacements in both the S1 and the S4 pockets. Structure-activity relationships were established to reveal and quantify contributions to the binding free enthalpy, resulting from single-atom replacements or positional changes in the ligands. A series of high-affinity ligands with inhibitory constants down to K(i) =2 nM were obtained and their proposed binding geometries confirmed by X-ray co-crystal structures of protein-ligand complexes.


==Function==
Molecular Recognition at the Active Site of Factor Xa: Cation-pi Interactions, Stacking on Planar Peptide Surfaces, and Replacement of Structural Water.,Salonen LM, Holland MC, Kaib PS, Haap W, Benz J, Mary JL, Kuster O, Schweizer WB, Banner DW, Diederich F Chemistry. 2011 Dec 9. doi: 10.1002/chem.201102571. PMID:22162109<ref>PMID:22162109</ref>
[[http://www.uniprot.org/uniprot/FA10_HUMAN 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.  


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[2y5h]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Y5H OCA].
</div>


==See Also==
==See Also==
*[[Factor Xa|Factor Xa]]
*[[Factor Xa|Factor Xa]]
 
== References ==
==Reference==
<references/>
<ref group="xtra">PMID:022162109</ref><references group="xtra"/><references/>
__TOC__
</StructureSection>
[[Category: Coagulation factor Xa]]
[[Category: Coagulation factor Xa]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Banner, D W.]]
[[Category: Banner, D W]]
[[Category: Benz, J.]]
[[Category: Benz, J]]
[[Category: Diederich, F.]]
[[Category: Diederich, F]]
[[Category: Haap, W.]]
[[Category: Haap, W]]
[[Category: Holland, M C.]]
[[Category: Holland, M C]]
[[Category: Salonen, L M.]]
[[Category: Salonen, L M]]
[[Category: Blood clotting]]
[[Category: Blood clotting]]
[[Category: Blood coagulation]]
[[Category: Blood coagulation]]

Revision as of 17:07, 18 December 2014

FACTOR XA - CATION INHIBITOR COMPLEXFACTOR XA - CATION INHIBITOR COMPLEX

Structural highlights

2y5h 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.
Ligands:,
Activity:Coagulation factor Xa, with EC number 3.4.21.6
Resources:FirstGlance, OCA, RCSB, PDBsum

Disease

[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.

Publication Abstract from PubMed

Factor Xa, a serine protease from the blood coagulation cascade, is an ideal enzyme for molecular recognition studies, as its active site is highly shape-persistent and features distinct, concave sub-pockets. We developed a family of non-peptidic, small-molecule inhibitors with a central tricyclic core orienting a neutral heterocyclic substituent into the S1 pocket and a quaternary ammonium ion into the aromatic box in the S4 pocket. The substituents were systematically varied to investigate cation-pi interactions in the S4 pocket, optimal heterocyclic stacking on the flat peptide walls lining the S1 pocket, and potential water replacements in both the S1 and the S4 pockets. Structure-activity relationships were established to reveal and quantify contributions to the binding free enthalpy, resulting from single-atom replacements or positional changes in the ligands. A series of high-affinity ligands with inhibitory constants down to K(i) =2 nM were obtained and their proposed binding geometries confirmed by X-ray co-crystal structures of protein-ligand complexes.

Molecular Recognition at the Active Site of Factor Xa: Cation-pi Interactions, Stacking on Planar Peptide Surfaces, and Replacement of Structural Water.,Salonen LM, Holland MC, Kaib PS, Haap W, Benz J, Mary JL, Kuster O, Schweizer WB, Banner DW, Diederich F Chemistry. 2011 Dec 9. doi: 10.1002/chem.201102571. PMID:22162109[18]

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

See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ 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
  10. ↑ 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
  11. ↑ 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
  12. ↑ 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
  13. ↑ 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
  14. ↑ 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
  15. ↑ 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
  16. ↑ 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
  17. ↑ 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
  18. ↑ Salonen LM, Holland MC, Kaib PS, Haap W, Benz J, Mary JL, Kuster O, Schweizer WB, Banner DW, Diederich F. Molecular Recognition at the Active Site of Factor Xa: Cation-pi Interactions, Stacking on Planar Peptide Surfaces, and Replacement of Structural Water. Chemistry. 2011 Dec 9. doi: 10.1002/chem.201102571. PMID:22162109 doi:10.1002/chem.201102571

2y5h, resolution 1.33Å

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