2bqw: Difference between revisions

From Proteopedia
Jump to navigation Jump to search
← Older editNewer edit →
No edit summary
No edit summary
Line 1: Line 1:


==CRYSTAL STRUCTURE OF FACTOR XA IN COMPLEX WITH COMPOUND 45==
==CRYSTAL STRUCTURE OF FACTOR XA IN COMPLEX WITH COMPOUND 45==
<StructureSection load='2bqw' size='340' side='right' caption='[[2bqw]], [[Resolution|resolution]] 2.95&Aring;' scene=''>
<StructureSection load='2bqw' size='340' side='right'caption='[[2bqw]], [[Resolution|resolution]] 2.95&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[2bqw]] 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=2BQW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2BQW FirstGlance]. <br>
<table><tr><td colspan='2'>[[2bqw]] 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=2BQW OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=2BQW FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=IIE:1-{2-[(4-CHLOROPHENYL)AMINO]-2-OXOETHYL}-N-(1-ISOPROPYLPIPERIDIN-4-YL)-1H-INDOLE-2-CARBOXAMIDE'>IIE</scene></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=IIE:1-{2-[(4-CHLOROPHENYL)AMINO]-2-OXOETHYL}-N-(1-ISOPROPYLPIPERIDIN-4-YL)-1H-INDOLE-2-CARBOXAMIDE'>IIE</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1c5m|1c5m]], [[1ezq|1ezq]], [[1f0r|1f0r]], [[1f0s|1f0s]], [[1fax|1fax]], [[1fjs|1fjs]], [[1fxy|1fxy]], [[1g2l|1g2l]], [[1g2m|1g2m]], [[1hcg|1hcg]], [[1ioe|1ioe]], [[1iqe|1iqe]], [[1iqf|1iqf]], [[1iqg|1iqg]], [[1iqh|1iqh]], [[1iqi|1iqi]], [[1iqj|1iqj]], [[1iqk|1iqk]], [[1iql|1iql]], [[1iqm|1iqm]], [[1iqn|1iqn]], [[1ksn|1ksn]], [[1kye|1kye]], [[1lpg|1lpg]], [[1lpk|1lpk]], [[1lpz|1lpz]], [[1lqd|1lqd]], [[1mq5|1mq5]], [[1mq6|1mq6]], [[1msx|1msx]], [[1nfu|1nfu]], [[1nfw|1nfw]], [[1nfx|1nfx]], [[1nfy|1nfy]], [[1nl8|1nl8]], [[1p0s|1p0s]], [[1v3x|1v3x]], [[1xka|1xka]], [[1xkb|1xkb]], [[2bmg|2bmg]], [[2boh|2boh]], [[2bok|2bok]], [[2bq6|2bq6]], [[2bq7|2bq7]]</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1c5m|1c5m]], [[1ezq|1ezq]], [[1f0r|1f0r]], [[1f0s|1f0s]], [[1fax|1fax]], [[1fjs|1fjs]], [[1fxy|1fxy]], [[1g2l|1g2l]], [[1g2m|1g2m]], [[1hcg|1hcg]], [[1ioe|1ioe]], [[1iqe|1iqe]], [[1iqf|1iqf]], [[1iqg|1iqg]], [[1iqh|1iqh]], [[1iqi|1iqi]], [[1iqj|1iqj]], [[1iqk|1iqk]], [[1iql|1iql]], [[1iqm|1iqm]], [[1iqn|1iqn]], [[1ksn|1ksn]], [[1kye|1kye]], [[1lpg|1lpg]], [[1lpk|1lpk]], [[1lpz|1lpz]], [[1lqd|1lqd]], [[1mq5|1mq5]], [[1mq6|1mq6]], [[1msx|1msx]], [[1nfu|1nfu]], [[1nfw|1nfw]], [[1nfx|1nfx]], [[1nfy|1nfy]], [[1nl8|1nl8]], [[1p0s|1p0s]], [[1v3x|1v3x]], [[1xka|1xka]], [[1xkb|1xkb]], [[2bmg|2bmg]], [[2boh|2boh]], [[2bok|2bok]], [[2bq6|2bq6]], [[2bq7|2bq7]]</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='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=2bqw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2bqw OCA], [http://pdbe.org/2bqw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2bqw RCSB], [http://www.ebi.ac.uk/pdbsum/2bqw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2bqw ProSAT]</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=2bqw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2bqw OCA], [http://pdbe.org/2bqw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2bqw RCSB], [http://www.ebi.ac.uk/pdbsum/2bqw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2bqw ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
Line 41: Line 41:
[[Category: Coagulation factor Xa]]
[[Category: Coagulation factor Xa]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Bauer, A]]
[[Category: Bauer, A]]
[[Category: Czech, J]]
[[Category: Czech, J]]

Revision as of 10:52, 4 November 2020

CRYSTAL STRUCTURE OF FACTOR XA IN COMPLEX WITH COMPOUND 45CRYSTAL STRUCTURE OF FACTOR XA IN COMPLEX WITH COMPOUND 45

Structural highlights

2bqw 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, PDBe, RCSB, PDBsum, ProSAT

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.

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

Structure-activity relationships within a series of highly potent 2-carboxyindole-based factor Xa inhibitors incorporating a neutral P1 ligand are described with particular emphasis on the structural requirements for addressing subpockets of the factor Xa enzyme. Interactions with the subpockets were probed by systematic substitution of the 2-carboxyindole scaffold, in combination with privileged P1 and P4 substituents. Combining the most favorable substituents at the indole nucleus led to the discovery of a remarkably potent factor Xa inhibitor displaying a K(i) value of 0.07 nM. X-ray crystallography of inhibitors bound to factor Xa revealed substituent-dependent switching of the inhibitor binding mode and provided a rationale for the SAR obtained. These results underscore the key role played by the P1 ligand not only in determining the binding affinity of the inhibitor by direct interaction but also in modifying the binding mode of the whole scaffold, resulting in a nonlinear SAR.

Probing the subpockets of factor Xa reveals two binding modes for inhibitors based on a 2-carboxyindole scaffold: a study combining structure-activity relationship and X-ray crystallography.,Nazare M, Will DW, Matter H, Schreuder H, Ritter K, Urmann M, Essrich M, Bauer A, Wagner M, Czech J, Lorenz M, Laux V, Wehner V J Med Chem. 2005 Jul 14;48(14):4511-25. PMID:15999990[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. ↑ Nazare M, Will DW, Matter H, Schreuder H, Ritter K, Urmann M, Essrich M, Bauer A, Wagner M, Czech J, Lorenz M, Laux V, Wehner V. Probing the subpockets of factor Xa reveals two binding modes for inhibitors based on a 2-carboxyindole scaffold: a study combining structure-activity relationship and X-ray crystallography. J Med Chem. 2005 Jul 14;48(14):4511-25. PMID:15999990 doi:http://dx.doi.org/10.1021/jm0490540

2bqw, resolution 2.95Å

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA
Retrieved from "https://proteopedia.openfox.io/wiki/index.php?title=2bqw&oldid=3312310"