View source for 5egm


==Development of a novel tricyclic class of potent and selective FIXa inhibitors==
<StructureSection load='5egm' size='340' side='right' caption='[[5egm]], [[Resolution|resolution]] 1.84&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5egm]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EGM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5EGM FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5NY:2-CHLORANYL-~{N}-[(7~{S})-2-METHYL-7-PHENYL-10-(1~{H}-1,2,3,4-TETRAZOL-5-YL)-8,9-DIHYDRO-6~{H}-PYRIDO[1,2-A]INDOL-7-YL]-4-(1,2,4-TRIAZOL-4-YL)BENZAMIDE'>5NY</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NHE:2-[N-CYCLOHEXYLAMINO]ETHANE+SULFONIC+ACID'>NHE</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">F9 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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_IXa Coagulation factor IXa], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.22 3.4.21.22] </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=5egm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5egm OCA], [http://pdbe.org/5egm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5egm RCSB], [http://www.ebi.ac.uk/pdbsum/5egm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5egm ProSAT]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/FA9_HUMAN FA9_HUMAN]] Defects in F9 are the cause of recessive X-linked hemophilia B (HEMB) [MIM:[http://omim.org/entry/306900 306900]]; also known as Christmas disease.<ref>PMID:8295821</ref> <ref>PMID:2592373</ref> <ref>PMID:2743975</ref> <ref>PMID:6603618</ref> <ref>PMID:3009023</ref> <ref>PMID:3790720</ref> <ref>PMID:3401602</ref> <ref>PMID:3243764</ref> <ref>PMID:2713493</ref> <ref>PMID:2714791</ref> <ref>PMID:2773937</ref> <ref>PMID:2775660</ref> <ref>PMID:2753873</ref> <ref>PMID:2738071</ref> <ref>PMID:2472424</ref> <ref>PMID:2339358</ref> <ref>PMID:2372509</ref> <ref>PMID:2162822</ref> <ref>PMID:1958666</ref> <ref>PMID:1902289</ref> <ref>PMID:1346975</ref> <ref>PMID:1615485</ref> <ref>PMID:8257988</ref> <ref>PMID:8076946</ref> <ref>PMID:8199596</ref> <ref>PMID:7981722</ref> <ref>PMID:8680410</ref> <ref>PMID:9222764</ref> <ref>PMID:9590153</ref> <ref>PMID:9452115</ref> <ref>PMID:9600455</ref> <ref>PMID:10698280</ref> <ref>PMID:10094553</ref> <ref>PMID:11122099</ref> <ref>PMID:12588353</ref> <ref>PMID:12604421</ref>   Note=Mutations in position 43 (Oxford-3, San Dimas) and 46 (Cambridge) prevents cleavage of the propeptide, mutation in position 93 (Alabama) probably fails to bind to cell membranes, mutation in position 191 (Chapel-Hill) or in position 226 (Nagoya OR Hilo) prevent cleavage of the activation peptide.  Defects in F9 are the cause of thrombophilia due to factor IX defect (THPH8) [MIM:[http://omim.org/entry/300807 300807]]. A hemostatic disorder characterized by a tendency to thrombosis.<ref>PMID:19846852</ref>  
== Function ==
[[http://www.uniprot.org/uniprot/FA9_HUMAN FA9_HUMAN]] Factor IX is a vitamin K-dependent plasma protein that participates in the intrinsic pathway of blood coagulation by converting factor X to its active form in the presence of Ca(2+) ions, phospholipids, and factor VIIIa. 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Using structure based drug design, a novel class of potent coagulation factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds were evaluated in rat IV/PO pharmacokinetic (PK) studies and demonstrated desirable oral PK profiles. Finally, the pharmacodynamics (PD) of this class of molecules were evaluated in thrombin generation assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.

Development of a novel tricyclic class of potent and selective FIXa inhibitors.,Meng D, Andre P, Bateman TJ, Berger R, Chen YH, Desai K, Dewnani S, Ellsworth K, Feng D, Geissler WM, Guo L, Hruza A, Jian T, Li H, Metzger J, Parker DL, Reichert P, Sherer EC, Smith CJ, Sonatore LM, Tschirret-Guth R, Wu J, Xu J, Zhang T, Campeau LC, Orr R, Poirier M, McCabe-Dunn J, Araki K, Nishimura T, Sakurada I, Hirabayashi T, Wood HB Bioorg Med Chem Lett. 2015 Nov 15;25(22):5437-43. doi:, 10.1016/j.bmcl.2015.07.078. Epub 2015 Jul 31. PMID:26318999<ref>PMID:26318999</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5egm" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Coagulation factor IXa]]
[[Category: Human]]
[[Category: Andre, P]]
[[Category: Araki, K]]
[[Category: Bateman, T J]]
[[Category: Berger, R]]
[[Category: Campeau, L]]
[[Category: Chen, Y]]
[[Category: Desai, K]]
[[Category: Dewnani, S]]
[[Category: Ellsworth, K]]
[[Category: Feng, D]]
[[Category: Geissler, W M]]
[[Category: Guo, L]]
[[Category: Hirabayashi, T]]
[[Category: Hruza, A]]
[[Category: Jian, T]]
[[Category: Li, H]]
[[Category: McCabe-Dunn, j]]
[[Category: Meng, D]]
[[Category: Nishimura, T]]
[[Category: Orr, R]]
[[Category: Parker, D L]]
[[Category: Poirier, M]]
[[Category: Reichert, P]]
[[Category: Sakurada, I]]
[[Category: Sherer, E C]]
[[Category: Smith, C J]]
[[Category: Sonatore, L M]]
[[Category: Tschirret-Guth, R]]
[[Category: Wood, H B]]
[[Category: Wu, J]]
[[Category: Xu, J]]
[[Category: Zhang, T]]
[[Category: Blood coagulation]]
[[Category: Coagulation factor]]
[[Category: Hydrolase-2 hydrolase inhibitor complex]]
[[Category: Hydrolase-hydrolase inhibitor complex]]
[[Category: Serine proteinase]]