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4a50

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Revision as of 12:59, 5 August 2016

Crystal structure of human kinesin Eg5 in complex with 2-Amino-5-(3-methylphenyl)-5,5-diphenylpentanoic acid

Structural highlights

4a50 is a 1 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:	2fky, 2x7c, 2xae, 1q0b, 2x2r, 2fl6, 2uym, 2x7d, 4a28, 2x7e, 1ii6, 2uyi, 2wog, 4a1z, 2g1q, 1yrs, 2gm1, 1x88, 2fl2, 4a2t, 4a51
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]

Publication Abstract from PubMed

The human mitotic kinesin Eg5 represents a novel mitotic spindle target for cancer chemotherapy. We previously identified S-trityl-l-cysteine (STLC) and related analogues as selective potent inhibitors of Eg5. We herein report on the development of a series of 4,4,4-triphenylbutan-1-amine inhibitors derived from the STLC scaffold. This new generation systematically improves on potency: the most potent C-trityl analogues exhibit K(i)(app) </= 10 nM and GI(50) approximately 50 nM, comparable to results from the phase II clinical benchmark ispinesib. Crystallographic studies reveal that they adopt the same overall binding configuration as S-trityl analogues at an allosteric site formed by loop L5 of Eg5. Evaluation of their druglike properties reveals favorable profiles for future development and, in the clinical candidate ispinesib, moderate hERG and CYP inhibition. One triphenylbutanamine analogue and ispinesib possess very good bioavailability (51% and 45%, respectively), with the former showing in vivo antitumor growth activity in nude mice xenograft studies.

Triphenylbutanamines: kinesin spindle protein inhibitors with in vivo antitumor activity.,Wang F, Good JA, Rath O, Kaan HY, Sutcliffe OB, Mackay SP, Kozielski F J Med Chem. 2012 Feb 23;55(4):1511-25. Epub 2012 Feb 13. PMID:22248262^[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
↑ Wang F, Good JA, Rath O, Kaan HY, Sutcliffe OB, Mackay SP, Kozielski F. Triphenylbutanamines: kinesin spindle protein inhibitors with in vivo antitumor activity. J Med Chem. 2012 Feb 23;55(4):1511-25. Epub 2012 Feb 13. PMID:22248262 doi:http://dx.doi.org/10.1021/jm201195m

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4a50"

@@ Line 1: / Line 1: @@
 ==Crystal structure of human kinesin Eg5 in complex with 2-Amino-5-(3-methylphenyl)-5,5-diphenylpentanoic acid==
 <StructureSection load='4a50' size='340' side='right' caption='[[4a50]], [[Resolution|resolution]] 2.75&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4a50]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4A50 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4A50 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4a50]] is a 1 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=4A50 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4A50 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=DQ6:(2S)-2-AMINO-5-(3-METHYLPHENYL)-5,5-DIPHENYLPROPANOIC+ACID'>DQ6</scene>, <scene name='pdbligand=DQ7:(2R)-2-AMINO-5-(3-METHYLPHENYL)-5,5-DIPHENYLPROPANOIC+ACID'>DQ7</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2fky|2fky]], [[2x7c|2x7c]], [[2xae|2xae]], [[1q0b|1q0b]], [[2x2r|2x2r]], [[2fl6|2fl6]], [[2uym|2uym]], [[2x7d|2x7d]], [[4a28|4a28]], [[2x7e|2x7e]], [[1ii6|1ii6]], [[2uyi|2uyi]], [[2wog|2wog]], [[4a1z|4a1z]], [[2g1q|2g1q]], [[1yrs|1yrs]], [[2gm1|2gm1]], [[1x88|1x88]], [[2fl2|2fl2]], [[4a2t|4a2t]], [[4a51|4a51]]</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=4a50 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4a50 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4a50 RCSB], [http://www.ebi.ac.uk/pdbsum/4a50 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=4a50 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4a50 OCA], [http://pdbe.org/4a50 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4a50 RCSB], [http://www.ebi.ac.uk/pdbsum/4a50 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4a50 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 19: / Line 20: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4a50" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 26: / Line 28: @@
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Kaan, H Y.K]]
 [[Category: Kozielski, F]]

4a50

From Proteopedia

Revision as of 12:59, 5 August 2016

Crystal structure of human kinesin Eg5 in complex with 2-Amino-5-(3-methylphenyl)-5,5-diphenylpentanoic acid

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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