2w3i: Difference between revisions

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-{{Seed}}
-[[Image:2w3i.jpg|left|200px]]
-<!--
+==Crystal Structure of FXa in complex with 4,4-disubstituted pyrrolidine-1,2-dicarboxamide inhibitor 2==
-The line below this paragraph, containing "STRUCTURE_2w3i", creates the "Structure Box" on the page.
+<StructureSection load='2w3i' size='340' side='right'caption='[[2w3i]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
-You may change the PDB parameter (which sets the PDB file loaded into the applet)
+== Structural highlights ==
-or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
+<table><tr><td colspan='2'>[[2w3i]] is a 2 chain structure with sequence from [https://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 [https://proteopedia.org/fgij/fg.htm?mol=2W3I FirstGlance]. <br>
-or leave the SCENE parameter empty for the default display.
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</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=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></td></tr>
-{{STRUCTURE_2w3i|  PDB=2w3i  |  SCENE=  }}
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2w3i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2w3i OCA], [https://pdbe.org/2w3i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2w3i RCSB], [https://www.ebi.ac.uk/pdbsum/2w3i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2w3i ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/FA10_HUMAN FA10_HUMAN] Defects in F10 are the cause of factor X deficiency (FA10D) [MIM:[https://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 ==
+[https://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/initialview03.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/main_output.php?pdb_ID=2w3i 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).
-===CRYSTAL STRUCTURE OF FXA IN COMPLEX WITH 4,4-DISUBSTITUTED PYRROLIDINE-1,2-DICARBOXAMIDE INHIBITOR 2===
+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>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 2w3i" style="background-color:#fffaf0;"></div>
-<!--
+==See Also==
-The line below this paragraph, {{ABSTRACT_PUBMED_19231206}}, adds the Publication Abstract to the page
+*[[Factor Xa|Factor Xa]]
-(as it appears on PubMed at http://www.pubmed.gov), where 19231206 is the PubMed ID number.
+== References ==
--->
+<references/>
-{{ABSTRACT_PUBMED_19231206}}
+__TOC__
+</StructureSection>
-==About this Structure==
-W3I is a 2 chains structure of sequences 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].
-==Reference==
-<ref group="xtra">PMID:19231206</ref><references group="xtra"/>
-[[Category: Coagulation factor Xa]]
 [[Category: Homo sapiens]]
-[[Category: Casimiro-Garcia, A.]]
+[[Category: Large Structures]]
-[[Category: Huis, C A.Van.]]
+[[Category: Casimiro-Garcia A]]
-[[Category: Mochalkin, I.]]
+[[Category: Mochalkin I]]
-[[Category: Zhang, E.]]
+[[Category: Van Huis CA]]
-[[Category: Blood clotting]]
+[[Category: Zhang E]]
-[[Category: Blood coagulation]]
-[[Category: Calcium]]
-[[Category: Cleavage on pair of basic residue]]
-[[Category: Drug design]]
-[[Category: Egf-like domain]]
-[[Category: Fxa coagulation factor inhibitor]]
-[[Category: Gamma-carboxyglutamic acid]]
-[[Category: Glycoprotein]]
-[[Category: Hydrolase]]
-[[Category: Hydroxylation]]
-[[Category: Polymorphism]]
-[[Category: Protease]]
-[[Category: Secreted]]
-[[Category: Serine protease]]
-[[Category: Zymogen]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Apr  9 12:18:33 2009''