We apologize for Proteopedia being slow to respond. For the past two years, a new implementation of Proteopedia has been being built. Soon, it will replace this 18-year old system. All existing content will be moved to the new system at a date that will be announced here.

2ieh

From Proteopedia

(Difference between revisions)

Jump to: navigation, search

Current revision

Crystal structure of human kinesin Eg5 in complex with (R)-mon97, a new monastrol-based inhibitor that binds as (R)-enantiomer

Structural highlights

2ieh is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.7Å
Ligands:	, , , , ,
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

Drugs that target mitotic spindle proteins have been proven useful for tackling tumor growth. Eg5, a kinesin-5 family member, represents a potential target, since its inhibition leads to prolonged mitotic arrest through the activation of the mitotic checkpoint and apoptotic cell death. Monastrol, a specific dihydropyrimidine inhibitor of Eg5, shows stereo-specificity, since predominantly the (S)-, but not the (R)-, enantiomer has been shown to be the biologically active compound in vitro and in cell-based assays. Here, we solved the crystal structure (2.7A) of the complex between human Eg5 and a new keto derivative of monastrol (named mon-97), a potent antimitotic inhibitor. Surprisingly, we identified the (R)-enantiomer bound in the active site, and not, as for monastrol, the (S)-enantiomer. The absolute configuration of this more active (R)-enantiomer has been unambiguously determined via chemical correlation and x-ray analysis. Unexpectedly, both the R- and the S-forms inhibit Eg5 ATPase activity with IC(50) values of 110 and 520 nM (basal assays) and 150 nm and 650 nm (microtubule-stimulated assays), respectively. However, the difference was large enough for the protein to select the (R)- over the (S)-enantiomer. Taken together, these results show that in this new monastrol family, both (R)- and (S)-enantiomers can be active as Eg5 inhibitors. This considerably broadens the alternatives for rational drug design.

Structure of human Eg5 in complex with a new monastrol-based inhibitor bound in the R configuration.,Garcia-Saez I, DeBonis S, Lopez R, Trucco F, Rousseau B, Thuery P, Kozielski F J Biol Chem. 2007 Mar 30;282(13):9740-7. Epub 2007 Jan 23. PMID:17251189^[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
↑ Garcia-Saez I, DeBonis S, Lopez R, Trucco F, Rousseau B, Thuery P, Kozielski F. Structure of human Eg5 in complex with a new monastrol-based inhibitor bound in the R configuration. J Biol Chem. 2007 Mar 30;282(13):9740-7. Epub 2007 Jan 23. PMID:17251189 doi:10.1074/jbc.M608883200

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/2ieh"

Categories: Homo sapiens | Large Structures | Garcia-Saez I | Kozielski F

@@ Line 1: / Line 1: @@
 ==Crystal structure of human kinesin Eg5 in complex with (R)-mon97, a new monastrol-based inhibitor that binds as (R)-enantiomer==
-<StructureSection load='2ieh' size='340' side='right' caption='[[2ieh]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
+<StructureSection load='2ieh' size='340' side='right'caption='[[2ieh]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2ieh]] 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=2IEH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2IEH FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2ieh]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2IEH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2IEH 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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=MOY:[(4R)-4-(3-HYDROXYPHENYL)-1,6-DIMETHYL-2-THIOXO-1,2,3,4-TETRAHYDROPYRIMIDIN-5-YL](PHENYL)METHANONE'>MOY</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">KIF11, EG5, KNSL1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=MOY:[(4R)-4-(3-HYDROXYPHENYL)-1,6-DIMETHYL-2-THIOXO-1,2,3,4-TETRAHYDROPYRIMIDIN-5-YL](PHENYL)METHANONE'>MOY</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Plus-end-directed_kinesin_ATPase Plus-end-directed kinesin ATPase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.6.4.4 3.6.4.4] </span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2ieh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ieh OCA], [https://pdbe.org/2ieh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ieh RCSB], [https://www.ebi.ac.uk/pdbsum/2ieh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ieh ProSAT]</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=2ieh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ieh OCA], [http://pdbe.org/2ieh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2ieh RCSB], [http://www.ebi.ac.uk/pdbsum/2ieh PDBsum]</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>
+[https://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:[https://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>
+[https://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>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
 Check<jmol>
   <jmolCheckbox>
-    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ie/2ieh_consurf.spt"</scriptWhenChecked>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ie/2ieh_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
-</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2ieh ConSurf].
 <div style="clear:both"></div>
 <div style="background-color:#fffaf0;">
@@ Line 33: / Line 33: @@
 ==See Also==
-*[[Kinesin|Kinesin]]
+*[[Kinesin 3D Structures|Kinesin 3D Structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
-[[Category: Plus-end-directed kinesin ATPase]]
+[[Category: Large Structures]]
-[[Category: Garcia-Saez, I]]
+[[Category: Garcia-Saez I]]
-[[Category: Kozielski, F]]
+[[Category: Kozielski F]]
-[[Category: Beta-sheet core]]
-[[Category: Flanked by three alpha-helices on each side]]
-[[Category: Hydrolase]]

2ieh

From Proteopedia

Current revision

Crystal structure of human kinesin Eg5 in complex with (R)-mon97, a new monastrol-based inhibitor that binds as (R)-enantiomer

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox