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3l9h

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Revision as of 07:11, 2 January 2019

X-ray structure of mitotic kinesin-5 (KSP, KIF11, Eg5)in complex with the hexahydro-2H-pyrano[3,2-c]quinoline EMD 534085

Structural highlights

3l9h is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Gene:	EG5, KIF11, KNSL1, TRIP5 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[KIF11_HUMAN] Defects in KIF11 are the cause of microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR) [MIM: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.^[1]

Function

[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.^[2]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Here we describe the discovery and optimization of hexahydro-2H-pyrano[3,2-c]quinolines (HHPQs) as potent and selective inhibitors of the mitotic kinesin-5 originally found during a high-throughput screening (HTS) campaign sampling our in-house compound collection. The compounds optimized subsequently and characterized herein were potently inhibiting the ATPase activity of Kinesin-5 and also exhibited consistent cellular activity, in that cells arrested in mitosis and apoptosis induction could be observed. X-ray crystallographic data demonstrated that these inhibitors bind in an allosteric pocket of Kinesin-5 distant from the nucleotide and microtubule binding sites. The selected clinical candidate EMD 534085 caused strong growth inhibition in human tumor xenograft models using Colo 205 colon carcinoma cells at doses below 30mg/kg administered twice weekly without showing severe toxicity as determined by loss of body weight.

The discovery and optimization of hexahydro-2H-pyrano[3,2-c]quinolines (HHPQs) as potent and selective inhibitors of the mitotic kinesin-5.,Schiemann K, Finsinger D, Zenke F, Amendt C, Knochel T, Bruge D, Buchstaller HP, Emde U, Stahle W, Anzali S Bioorg Med Chem Lett. 2010 Mar 1;20(5):1491-5. Epub 2010 Jan 25. PMID:20149654^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Ostergaard P, Simpson MA, Mendola A, Vasudevan P, Connell FC, van Impel A, Moore AT, Loeys BL, Ghalamkarpour A, Onoufriadis A, Martinez-Corral I, Devery S, Leroy JG, van Laer L, Singer A, Bialer MG, McEntagart M, Quarrell O, Brice G, Trembath RC, Schulte-Merker S, Makinen T, Vikkula M, Mortimer PS, Mansour S, Jeffery S. Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy. Am J Hum Genet. 2012 Feb 10;90(2):356-62. doi: 10.1016/j.ajhg.2011.12.018. Epub, 2012 Jan 26. PMID:22284827 doi:10.1016/j.ajhg.2011.12.018
↑ Rapley J, Nicolas M, Groen A, Regue L, Bertran MT, Caelles C, Avruch J, Roig J. The NIMA-family kinase Nek6 phosphorylates the kinesin Eg5 at a novel site necessary for mitotic spindle formation. J Cell Sci. 2008 Dec 1;121(Pt 23):3912-21. doi: 10.1242/jcs.035360. Epub 2008 Nov, 11. PMID:19001501 doi:10.1242/jcs.035360
↑ Schiemann K, Finsinger D, Zenke F, Amendt C, Knochel T, Bruge D, Buchstaller HP, Emde U, Stahle W, Anzali S. The discovery and optimization of hexahydro-2H-pyrano[3,2-c]quinolines (HHPQs) as potent and selective inhibitors of the mitotic kinesin-5. Bioorg Med Chem Lett. 2010 Mar 1;20(5):1491-5. Epub 2010 Jan 25. PMID:20149654 doi:10.1016/j.bmcl.2010.01.110

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3l9h"

@@ Line 1: / Line 1: @@
 ==X-ray structure of mitotic kinesin-5 (KSP, KIF11, Eg5)in complex with the hexahydro-2H-pyrano[3,2-c]quinoline EMD 534085==
 <StructureSection load='3l9h' size='340' side='right' caption='[[3l9h]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=EMQ:1-[2-(DIMETHYLAMINO)ETHYL]-3-{[(2R,4AS,5R,10BS)-5-PHENYL-9-(TRIFLUOROMETHYL)-3,4,4A,5,6,10B-HEXAHYDRO-2H-PYRANO[3,2-C]QUINOLIN-2-YL]METHYL}UREA'>EMQ</scene></td></tr>
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">EG5, KIF11, KNSL1, TRIP5 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=3l9h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3l9h OCA], [http://pdbe.org/3l9h PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3l9h RCSB], [http://www.ebi.ac.uk/pdbsum/3l9h PDBsum]</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=3l9h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3l9h OCA], [http://pdbe.org/3l9h PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3l9h RCSB], [http://www.ebi.ac.uk/pdbsum/3l9h PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3l9h ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 15: / Line 16: @@
 Check<jmol>
   <jmolCheckbox>
-    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/l9/3l9h_consurf.spt"</scriptWhenChecked>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/l9/3l9h_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
@@ Line 39: / Line 40: @@
 [[Category: Human]]
 [[Category: Knoechel, T]]
+[[Category: Acetylation]]
 [[Category: Atp-binding]]
 [[Category: Cell cycle]]
 [[Category: Cell division]]
+[[Category: Coiled coil]]
 [[Category: Eg5]]
 [[Category: Emd 534085]]
@@ Line 50: / Line 53: @@
 [[Category: Nucleotide-binding]]
 [[Category: Phosphoprotein]]
+[[Category: Polymorphism]]
 [[Category: Small molecule inhibitor]]

3l9h

From Proteopedia

Revision as of 07:11, 2 January 2019

X-ray structure of mitotic kinesin-5 (KSP, KIF11, Eg5)in complex with the hexahydro-2H-pyrano[3,2-c]quinoline EMD 534085

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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