We apologize for Proteopedia being slow to respond. For the past two years, a new implementation of Proteopedia has been being built. Soon, it will replace this 18-year old system. All existing content will be moved to the new system at a date that will be announced here.

1lpg

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Current revision (08:25, 10 April 2024) (edit) (undo)
 
(17 intermediate revisions not shown.)
Line 1: Line 1:
-
[[Image:1lpg.jpg|left|200px]]<br /><applet load="1lpg" size="350" color="white" frame="true" align="right" spinBox="true"
 
-
caption="1lpg, resolution 2.00&Aring;" />
 
-
'''CRYSTAL STRUCTURE OF FXA IN COMPLEX WITH 79.'''<br />
 
-
==Overview==
+
==CRYSTAL STRUCTURE OF FXA IN COMPLEX WITH 79.==
-
A series of 138 nonchiral 3-amidinobenzyl-1H-indole-2-carboxamides and, analogues as inhibitors of the blood coagulation enzyme factor Xa (fXa), were designed, synthesized, and investigated by X-ray structure analysis, and 3D quantitative structure-activity relationship (QSAR) studies (CoMFA, CoMSIA) in order to identify important protein-ligand interactions, responsible for biological affinity and selectivity. Several compounds, from this series are highly potent and selective inhibitors of this, important enzyme linking extrinsic and intrinsic coagulation pathways. To, rationalize biological affinity and to provide guidelines for further, design, all compounds were docked into the factor Xa binding site. Those, docking studies were based on X-ray structures of factor Xa in complex, with literature-known inhibitors. It was possible to validate those, binding modes by four X-ray crystal structures of representative ligands, in factor Xa, while one ligand was additionally crystallized in trypsin to, rationalize requirements for selective factor Xa inhibition. The 3D-QSAR, models based on a superposition rule derived from these docking studies, were validated using conventional and cross-validated r(2) values using, the leave-one-out method and repeated analyses using two randomly chosen, cross-validation groups plus randomization of biological activities. This, led to consistent and highly predictive 3D-QSAR models with good, correlation coefficients for both CoMFA and CoMSIA, which were found to, correspond to experimentally determined factor Xa binding site topology in, terms of steric, electrostatic, and hydrophobic complementarity. Subsets, selected as smaller training sets using 2D fingerprints and maximum, dissimilarity methods resulted in 3D-QSAR models with remarkable, correlation coefficients and a high predictive power. The final, quantitative SAR information agrees with all experimental data for the, binding topology and thus provides reasonable activity predictions for, novel factor Xa inhibitors.
+
<StructureSection load='1lpg' size='340' side='right'caption='[[1lpg]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 +
== Structural highlights ==
 +
<table><tr><td colspan='2'>[[1lpg]] 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=1LPG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1LPG FirstGlance]. <br>
 +
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2&#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=IMA:[4-({[5-BENZYLOXY-1-(3-CARBAMIMIDOYL-BENZYL)-1H-INDOLE-2-CARBONYL]-AMINO}-METHYL)-PHENYL]-TRIMETHYL-AMMONIUM'>IMA</scene></td></tr>
 +
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1lpg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1lpg OCA], [https://pdbe.org/1lpg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1lpg RCSB], [https://www.ebi.ac.uk/pdbsum/1lpg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1lpg 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/lp/1lpg_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/main_output.php?pdb_ID=1lpg ConSurf].
 +
<div style="clear:both"></div>
-
==Disease==
+
==See Also==
-
Known disease associated with this structure: Factor X deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=227600 227600]]
+
*[[Factor Xa|Factor Xa]]
-
 
+
== References ==
-
==About this Structure==
+
<references/>
-
1LPG is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=CA:'>CA</scene> and <scene name='pdbligand=IMA:'>IMA</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1LPG OCA].
+
__TOC__
-
 
+
</StructureSection>
-
==Reference==
+
-
Design and quantitative structure-activity relationship of 3-amidinobenzyl-1H-indole-2-carboxamides as potent, nonchiral, and selective inhibitors of blood coagulation factor Xa., Matter H, Defossa E, Heinelt U, Blohm PM, Schneider D, Muller A, Herok S, Schreuder H, Liesum A, Brachvogel V, Lonze P, Walser A, Al-Obeidi F, Wildgoose P, J Med Chem. 2002 Jun 20;45(13):2749-69. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12061878 12061878]
+
-
[[Category: Coagulation factor Xa]]
+
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
-
[[Category: Protein complex]]
+
[[Category: Large Structures]]
-
[[Category: Brachvogel, V.]]
+
[[Category: Brachvogel V]]
-
[[Category: Liesum, A.]]
+
[[Category: Liesum A]]
-
[[Category: Schreuder, H.A.]]
+
[[Category: Schreuder HA]]
-
[[Category: CA]]
+
-
[[Category: IMA]]
+
-
[[Category: blood coagulation factor]]
+
-
[[Category: protein inhibitor complex]]
+
-
[[Category: serine proteinase]]
+
-
 
+
-
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 16:19:42 2008''
+

Current revision

CRYSTAL STRUCTURE OF FXA IN COMPLEX WITH 79.

PDB ID 1lpg

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1lpg"
Personal tools