View source for 2xae


==Crystal structure of human kinesin Eg5 in complex with (R)-2-amino-3-((S)-2-methyl-1,1-diphenylbutylthio)propanoic acid==
<StructureSection load='2xae' size='340' side='right'caption='[[2xae]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2xae]] is a 3 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=2XAE OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=2XAE FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2XA:(2R)-2-AMINO-3-[(4-CHLOROPHENYL)-DIPHENYL-METHYL]SULFANYL-PROPANOIC+ACID'>2XA</scene>, <scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1ii6|1ii6]], [[2x7e|2x7e]], [[2fky|2fky]], [[2uyi|2uyi]], [[2x7c|2x7c]], [[1q0b|1q0b]], [[2wog|2wog]], [[2x2r|2x2r]], [[2g1q|2g1q]], [[2uym|2uym]], [[1yrs|1yrs]], [[2fl6|2fl6]], [[2gm1|2gm1]], [[1x88|1x88]], [[2x7d|2x7d]], [[2fl2|2fl2]]</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=2xae FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xae OCA], [http://pdbe.org/2xae PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2xae RCSB], [http://www.ebi.ac.uk/pdbsum/2xae PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2xae ProSAT]</span></td></tr>
</table>
== Disease ==
[[http://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:[http://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 ==
[[http://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>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The mitotic spindle is a validated target for cancer chemotherapy. Drugs such as taxanes and vinca alkaloids specifically target microtubules and cause the mitotic spindle to collapse. However, toxicity and resistance are problems associated with these drugs. Thus, alternative approaches to inhibiting the mitotic spindle are being pursued. These include targeting Eg5, a human kinesin involved in the formation of the bipolar spindle. We previously identified S-trityl-l-cysteine (STLC) as a potent allosteric inhibitor of Eg5. Here, we report the synthesis of a new series of STLC-like compounds with in vitro inhibition in the low nanomolar range. We also performed a multidrug resistance study in cell lines overexpressing P-glycoprotein and showed that some of these inhibitors may have the potential to overcome susceptibility to this efflux pump. Finally, we performed molecular docking of the compounds and determined the structures of two Eg5-inhibitor complexes to explain the structure-activity relationship of these compounds.

Structure-Activity Relationship and Multidrug Resistance Study of New S-trityl-l-Cysteine Derivatives As Inhibitors of Eg5.,Kaan HY, Weiss J, Menger D, Ulaganathan V, Tkocz K, Laggner C, Popowycz F, Joseph B, Kozielski F J Med Chem. 2011 Mar 24;54(6):1576-1586. Epub 2011 Feb 23. PMID:21344920<ref>PMID:21344920</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2xae" style="background-color:#fffaf0;"></div>

==See Also==
*[[Kinesin 3D Structures|Kinesin 3D Structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Joseph, B]]
[[Category: Kaan, H Y.K]]
[[Category: Kozielski, F]]
[[Category: Laggner, C]]
[[Category: Menger, D]]
[[Category: Popowycz, F]]
[[Category: Tkocz, K]]
[[Category: Ulaganathan, V]]
[[Category: Weiss, J]]
[[Category: Cell cycle]]
[[Category: Ksp]]
[[Category: Mitosis]]