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{{STRUCTURE_2w3i|  PDB=2w3i  |  SCENE=  }}
==CRYSTAL STRUCTURE OF FXA IN COMPLEX WITH 4,4-DISUBSTITUTED PYRROLIDINE-1,2-DICARBOXAMIDE INHIBITOR 2==
===CRYSTAL STRUCTURE OF FXA IN COMPLEX WITH 4,4-DISUBSTITUTED PYRROLIDINE-1,2-DICARBOXAMIDE INHIBITOR 2===
<StructureSection load='2w3i' size='340' side='right' caption='[[2w3i]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
{{ABSTRACT_PUBMED_19231206}}
== Structural highlights ==
 
<table><tr><td colspan='2'>[[2w3i]] 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=2W3I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2W3I FirstGlance]. <br>
==Disease==
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=L1C:(2R,4S)-N^1^-(4-CHLOROPHENYL)-4-(2,4-DIFLUOROPHENYL)-4-HYDROXY-N^2^-(2-OXO-2H-1,3-BIPYRIDIN-6-YL)PYRROLIDINE-1,2-DICARBOXAMIDE'>L1C</scene><br>
[[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><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1wu1|1wu1]], [[2j34|2j34]], [[2bq7|2bq7]], [[2vwo|2vwo]], [[1nfw|1nfw]], [[1xka|1xka]], [[2vvv|2vvv]], [[2gd4|2gd4]], [[1lpg|1lpg]], [[1msx|1msx]], [[2vvu|2vvu]], [[1p0s|1p0s]], [[2g00|2g00]], [[1mq6|1mq6]], [[1xkb|1xkb]], [[1iqe|1iqe]], [[1g2m|1g2m]], [[2vh0|2vh0]], [[1nfy|1nfy]], [[2uwl|2uwl]], [[2bok|2bok]], [[1lpz|1lpz]], [[1hcg|1hcg]], [[1z6e|1z6e]], [[2jkh|2jkh]], [[2uwp|2uwp]], [[1g2l|1g2l]], [[1nfu|1nfu]], [[2bq6|2bq6]], [[1fax|1fax]], [[1iqf|1iqf]], [[1nl8|1nl8]], [[1iqg|1iqg]], [[1iqh|1iqh]], [[1lqd|1lqd]], [[2uwo|2uwo]], [[1c5m|1c5m]], [[1ioe|1ioe]], [[1f0s|1f0s]], [[1f0r|1f0r]], [[1mq5|1mq5]], [[2bmg|2bmg]], [[1iqn|1iqn]], [[2bqw|2bqw]], [[1iqm|1iqm]], [[1ezq|1ezq]], [[2vwl|2vwl]], [[2vh6|2vh6]], [[1fjs|1fjs]], [[1lpk|1lpk]], [[2j4i|2j4i]], [[1nfx|1nfx]], [[2vwn|2vwn]], [[1iqj|1iqj]], [[2j94|2j94]], [[2cji|2cji]], [[2j95|2j95]], [[2j38|2j38]], [[2boh|2boh]], [[2w26|2w26]], [[2vvc|2vvc]], [[1iqi|1iqi]], [[2vwm|2vwm]], [[1kye|1kye]], [[1iqk|1iqk]], [[1v3x|1v3x]], [[2fzz|2fzz]], [[2j2u|2j2u]], [[1iql|1iql]], [[1ksn|1ksn]], [[2w3k|2w3k]]</td></tr>
<tr><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><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2w3i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2w3i OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2w3i RCSB], [http://www.ebi.ac.uk/pdbsum/2w3i 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.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/w3/2w3i_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Aiming to improve upon previously disclosed Factor Xa inhibitors, a series of 4,4-disubstituted pyrrolidine-1,2-dicarboxamides were explored with the intent of increasing the projected human half-life versus 5 (projected human t(1/2)=6 h). A stereospecific route to compounds containing a 4-aryl-4-hydroxypyrrolidine scaffold was developed, resulting in several compounds that demonstrated an increase in the half-life as well as an increase in the in vitro potency compared to 5. Reported herein is the discovery of 26, containing a (2R,4S)-4-hydroxy-4-(2,4-difluorophenyl)-pyrrolidine scaffold, which is a selective, orally bioavailable, efficacious Factor Xa inhibitor that appears suitable for a once-daily dosing (projected human t(1/2)=23 h).


==Function==
Exploration of 4,4-disubstituted pyrrolidine-1,2-dicarboxamides as potent, orally active Factor Xa inhibitors with extended duration of action.,Van Huis CA, Casimiro-Garcia A, Bigge CF, Cody WL, Dudley DA, Filipski KJ, Heemstra RJ, Kohrt JT, Leadley RJ Jr, Narasimhan LS, McClanahan T, Mochalkin I, Pamment M, Peterson JT, Sahasrabudhe V, Schaum RP, Edmunds JJ Bioorg Med Chem. 2009 Mar 15;17(6):2501-11. Epub 2009 Feb 3. PMID:19231206<ref>PMID:19231206</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>
[[2w3i]] 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=2W3I OCA].
</div>


==See Also==
==See Also==
*[[Factor Xa|Factor Xa]]
*[[Factor Xa|Factor Xa]]
 
== References ==
==Reference==
<references/>
<ref group="xtra">PMID:019231206</ref><references group="xtra"/><references/>
__TOC__
</StructureSection>
[[Category: Coagulation factor Xa]]
[[Category: Coagulation factor Xa]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]

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