2gm1: Difference between revisions

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-[[Image:2gm1.gif|left|200px]]<br />
-<applet load="2gm1" size="450" color="white" frame="true" align="right" spinBox="true"
-caption="2gm1, resolution 2.30&Aring;" />
-'''Crystal structure of the mitotic kinesin eg5 in complex with mg-adp and n-(3-aminopropyl)-n-((3-benzyl-5-chloro-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)(cyclopropyl)methyl)-4-methylbenzamide'''<br />
-==Overview==
+==Crystal structure of the mitotic kinesin eg5 in complex with mg-adp and n-(3-aminopropyl)-n-((3-benzyl-5-chloro-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)(cyclopropyl)methyl)-4-methylbenzamide==
-Synthesis and SAR of substituted pyrrolotriazine-4-one analogues as Eg5, inhibitors are described. Many of these analogues displayed potent, inhibitory activities in the Eg5 ATPase and A2780 cell proliferation, assays. In addition, pyrrolotriazine-4-one analogue 26 demonstrated in, vivo efficacy in an iv P388 murine leukemia model. Both NMR and X-ray, crystallographic studies revealed that these analogues bind to an, allosteric site on the Eg5 protein.
+<StructureSection load='2gm1' size='340' side='right'caption='[[2gm1]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[2gm1]] is a 4 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=2GM1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2GM1 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]] 2.3&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2AZ:N-(3-AMINOPROPYL)-N-[(R)-(3-BENZYL-5-CHLORO-4-OXO-3,4-DIHYDROPYRROLO[2,1-F][1,2,4]TRIAZIN-2-YL)(CYCLOPROPYL)METHYL]-4-METHYLBENZAMIDE'>2AZ</scene>, <scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=2gm1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2gm1 OCA], [https://pdbe.org/2gm1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2gm1 RCSB], [https://www.ebi.ac.uk/pdbsum/2gm1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2gm1 ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/KIF11_HUMAN KIF11_HUMAN] Defects in KIF11 are the cause of microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR) [MIM:[https://omim.org/entry/152950 152950]. An autosomal dominant disorder that involves an overlapping but variable spectrum of central nervous system and ocular developmental anomalies. Microcephaly ranges from mild to severe and is often associated with mild to moderate developmental delay and a characteristic facial phenotype with upslanting palpebral fissures, broad nose with rounded tip, long philtrum with thin upper lip, prominent chin, and prominent ears. Chorioretinopathy is the most common eye abnormality, but retinal folds, microphthalmia, and myopic and hypermetropic astigmatism have also been reported, and some individuals have no overt ocular phenotype. Congenital lymphedema, when present, is typically confined to the dorsa of the feet, and lymphoscintigraphy reveals the absence of radioactive isotope uptake from the webspaces between the toes.<ref>PMID:22284827</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/KIF11_HUMAN KIF11_HUMAN] Motor protein required for establishing a bipolar spindle. Blocking of KIF11 prevents centrosome migration and arrest cells in mitosis with monoastral microtubule arrays.<ref>PMID:19001501</ref>
+== 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/gm/2gm1_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=2gm1 ConSurf].
+<div style="clear:both"></div>
-==About this Structure==
+==See Also==
-GM1 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with MG, 2AZ and ADP as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2GM1 OCA].
+*[[Kinesin 3D Structures|Kinesin 3D Structures]]
+== References ==
-==Reference==
+<references/>
-Synthesis and SAR of pyrrolotriazine-4-one based Eg5 inhibitors., Kim KS, Lu S, Cornelius LA, Lombardo LJ, Borzilleri RM, Schroeder GM, Sheng C, Rovnyak G, Crews D, Schmidt RJ, Williams DK, Bhide RS, Traeger SC, McDonnell PA, Mueller L, Sheriff S, Newitt JA, Pudzianowski AT, Yang Z, Wild R, Lee FY, Batorsky R, Ryder JS, Ortega-Nanos M, Shen H, Gottardis M, Roussell DL, Bioorg Med Chem Lett. 2006 Aug 1;16(15):3937-42. Epub 2006 May 30. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16730979 16730979]
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Single protein]]
+[[Category: Large Structures]]
-[[Category: Sheriff, S.]]
+[[Category: Sheriff S]]
-[[Category: 2AZ]]
-[[Category: ADP]]
-[[Category: MG]]
-[[Category: eg5 mg-adp complex inhibitor]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 22:20:03 2007''