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6g6z

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Eg5-inhibitor complex

Structural highlights

6g6z 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:	, ,
Gene:	KIF11, EG5, 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]

Publication Abstract from PubMed

The thiadiazole scaffold is an important core moiety in a variety of clinical drug candidates targeting a range of diseases. For example, the 2,4,5-substituted 1,3,4-thiadiazole scaffold is present in a lead compound and at least two clinical candidates targeting the human motor protein Eg5, against neoplastic diseases. An inhibitor named K858 has in vivo activity in various mouse xenografts whereas the clinical candidates (S)-ARRY-520 and (R)-Litronesib have entered clinical trials with the former one in phase III clinical trials either alone or in combination with a proteasome inhibitor against relapsed/refractory multiple myeloma. Astonishingly, structural data are lacking for all thiadiazole-containing Eg5 inhibitors. Here we report the structure determination of two crystal forms of the ternary Eg5-ADP-K858 complex, locking the motor in the so-called final inhibitor bound state, thus blocking ADP release, a crucial stage for Eg5 activity. K858 acts at the established allosteric inhibitor-binding pocket formed of helix alpha2, loop L5 and helix alpha3. The structure of the complex has far reaching consequences for thiadiazole containing Eg5 inhibitors. For example, we could rationalise the structure-activity relationship in the crucial 5-position of the thiadiazole scaffold and the complex will serve in the future as a basis for strucutre-based drug design.

Crystal structure of the Eg5 - K858 complex and implications for structure-based design of thiadiazole-containing inhibitors.,Talapatra SK, Tham CL, Guglielmi P, Cirilli R, Chandrasekaran B, Karpoormath R, Carradori S, Kozielski F Eur J Med Chem. 2018 Jul 4;156:641-651. doi: 10.1016/j.ejmech.2018.07.006. PMID:30031975^[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
↑ Talapatra SK, Tham CL, Guglielmi P, Cirilli R, Chandrasekaran B, Karpoormath R, Carradori S, Kozielski F. Crystal structure of the Eg5 - K858 complex and implications for structure-based design of thiadiazole-containing inhibitors. Eur J Med Chem. 2018 Jul 4;156:641-651. doi: 10.1016/j.ejmech.2018.07.006. PMID:30031975 doi:http://dx.doi.org/10.1016/j.ejmech.2018.07.006

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6g6z"

@@ Line 1: / Line 1: @@
 ==Eg5-inhibitor complex==
-<StructureSection load='6g6z' size='340' side='right' caption='[[6g6z]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
+<StructureSection load='6g6z' size='340' side='right'caption='[[6g6z]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6g6z]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6G6Z OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6G6Z FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6g6z]] 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=6G6Z OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6G6Z 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=EOK:(~{N}~{Z})-~{N}-[(5~{S})-4-ethanoyl-5-methyl-5-phenyl-1,3,4-thiadiazolidin-2-ylidene]ethanamide'>EOK</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=EOK:(~{N}~{Z})-~{N}-[(5~{S})-4-ethanoyl-5-methyl-5-phenyl-1,3,4-thiadiazolidin-2-ylidene]ethanamide'>EOK</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6g6z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g6z OCA], [http://pdbe.org/6g6z PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6g6z RCSB], [http://www.ebi.ac.uk/pdbsum/6g6z PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6g6z ProSAT]</span></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">KIF11, EG5, 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://proteopedia.org/fgij/fg.htm?mol=6g6z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g6z OCA], [http://pdbe.org/6g6z PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6g6z RCSB], [http://www.ebi.ac.uk/pdbsum/6g6z PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6g6z ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 24: / Line 25: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Kozielski, F]]
 [[Category: Talapatra, S K]]

6g6z

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Current revision

Eg5-inhibitor complex

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

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