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2x7e

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Revision as of 15:06, 8 July 2020

Crystal structure of human kinesin Eg5 in complex with (R)-fluorastrol

Structural highlights

2x7e 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:	, ,
Related:	1ii6, 2fky, 2uyi, 1q0b, 2wog, 2x2r, 2g1q, 2uym, 1yrs, 2fl6, 2gm1, 1x88, 2fl2, 2x7c, 2x7d
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

Human kinesin Eg5, which plays an essential role in mitosis by establishing the bipolar spindle, has proven to be an interesting drug target for the development of cancer chemotherapeutics. Here, we report the crystal structures of the Eg5 motor domain complexed with enastron, dimethylenastron, and fluorastrol. By comparing these structures to that of monastrol and mon-97, we identified the main reasons for increased potency of these new inhibitors, namely the better fit of the ligand to the allosteric binding site and the addition of fluorine atoms. We also noticed preferential binding of the S-enantiomer of enastron and dimethylenastron to Eg5, while the R-enantiomer of fluorastrol binds preferentially to Eg5. In addition, we performed a multidrug resistance (MDR) study in cell lines overexpressing P-glycoprotein (Pgp). We showed that one of these inhibitors may have the potential to overcome susceptibility to this efflux pump and hence overcome common resistance associated with tubulin-targeting drugs.

Structural Basis for Inhibition of Eg5 by Dihydropyrimidines: Stereoselectivity of Antimitotic Inhibitors Enastron, Dimethylenastron and Fluorastrol.,Kaan HY, Ulaganathan V, Rath O, Prokopcova H, Dallinger D, Kappe CO, Kozielski F J Med Chem. 2010 Jul 2. PMID:20597485^[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
↑ Kaan HY, Ulaganathan V, Rath O, Prokopcova H, Dallinger D, Kappe CO, Kozielski F. Structural Basis for Inhibition of Eg5 by Dihydropyrimidines: Stereoselectivity of Antimitotic Inhibitors Enastron, Dimethylenastron and Fluorastrol. J Med Chem. 2010 Jul 2. PMID:20597485 doi:10.1021/jm100421n

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/2x7e"

@@ Line 1: / Line 1: @@
 ==Crystal structure of human kinesin Eg5 in complex with (R)-fluorastrol==
-<StructureSection load='2x7e' size='340' side='right' caption='[[2x7e]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
+<StructureSection load='2x7e' size='340' side='right'caption='[[2x7e]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2x7e]] 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=2X7E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2X7E FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2x7e]] 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=2X7E OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=2X7E FirstGlance]. <br>
-</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=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=X7E:(4R)-5-[(S)-(3,4-DIFLUOROPHENYL)(HYDROXY)METHYL]-4-(3-HYDROXYPHENYL)-1,6-DIMETHYL-3,4-DIHYDROPYRIMIDINE-2(1H)-THIONE'>X7E</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=X7E:(4R)-5-[(S)-(3,4-DIFLUOROPHENYL)(HYDROXY)METHYL]-4-(3-HYDROXYPHENYL)-1,6-DIMETHYL-3,4-DIHYDROPYRIMIDINE-2(1H)-THIONE'>X7E</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1ii6|1ii6]], [[2fky|2fky]], [[2uyi|2uyi]], [[1q0b|1q0b]], [[2wog|2wog]], [[2x2r|2x2r]], [[2g1q|2g1q]], [[2uym|2uym]], [[1yrs|1yrs]], [[2fl6|2fl6]], [[2gm1|2gm1]], [[1x88|1x88]], [[2fl2|2fl2]], [[2x7c|2x7c]], [[2x7d|2x7d]]</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=2x7e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2x7e OCA], [http://pdbe.org/2x7e PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2x7e RCSB], [http://www.ebi.ac.uk/pdbsum/2x7e PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2x7e ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=2x7e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2x7e OCA], [http://pdbe.org/2x7e PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2x7e RCSB], [http://www.ebi.ac.uk/pdbsum/2x7e PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2x7e ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 33: / Line 33: @@
 ==See Also==
-*[[Kinesin|Kinesin]]
+*[[Kinesin 3D Structures|Kinesin 3D Structures]]
 == References ==
 <references/>
@@ Line 39: / Line 39: @@
 </StructureSection>
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Dallinger, D]]
 [[Category: Kaan, H Y.K]]

2x7e

From Proteopedia

Revision as of 15:06, 8 July 2020

Crystal structure of human kinesin Eg5 in complex with (R)-fluorastrol

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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