3cjo

From Proteopedia

(Difference between revisions)

Revision as of 11:24, 8 February 2016

Crystal structure of KSP in complex with inhibitor 30

Structural highlights

3cjo 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.
Ligands:	, ,
Gene:	KIF11, EG5, KNSL1, TRIP5 (Homo sapiens)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum

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

Inhibition of kinesin spindle protein (KSP) is a novel mechanism for treatment of cancer with the potential to overcome limitations associated with currently employed cytotoxic agents. Herein, we describe a C2-hydroxymethyl dihydropyrrole KSP inhibitor ( 11) that circumvents hERG channel binding and poor in vivo potency, issues that limited earlier compounds from our program. However, introduction of the C2-hydroxymethyl group caused 11 to be a substrate for cellular efflux by P-glycoprotein (Pgp). Utilizing knowledge garnered from previous KSP inhibitors, we found that beta-fluorination modulated the p K a of the piperidine nitrogen and reduced Pgp efflux, but the resulting compound ( 14) generated a toxic metabolite in vivo. Incorporation of fluorine in a strategic, metabolically benign position by synthesis of an N-methyl-3-fluoro-4-(aminomethyl)piperidine urea led to compound 30 that has an optimal in vitro and metabolic profile. Compound 30 (MK-0731) was recently studied in a phase I clinical trial in patients with taxane-refractory solid tumors.

Kinesin Spindle Protein (KSP) Inhibitors. 9. Discovery of (2S)-4-(2,5-Difluorophenyl)-N-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2- (hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (MK-0731) for the Treatment of Taxane-Refractory Cancer.,Cox CD, Coleman PJ, Breslin MJ, Whitman DB, Garbaccio RM, Fraley ME, Buser CA, Walsh ES, Hamilton K, Schaber MD, Lobell RB, Tao W, Davide JP, Diehl RE, Abrams MT, South VJ, Huber HE, Torrent M, Prueksaritanont T, Li C, Slaughter DE, Mahan E, Fernandez-Metzler C, Yan Y, Kuo LC, Kohl NE, Hartman GD J Med Chem. 2008 Jun 25;. PMID:18578472^[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
↑ Cox CD, Coleman PJ, Breslin MJ, Whitman DB, Garbaccio RM, Fraley ME, Buser CA, Walsh ES, Hamilton K, Schaber MD, Lobell RB, Tao W, Davide JP, Diehl RE, Abrams MT, South VJ, Huber HE, Torrent M, Prueksaritanont T, Li C, Slaughter DE, Mahan E, Fernandez-Metzler C, Yan Y, Kuo LC, Kohl NE, Hartman GD. Kinesin Spindle Protein (KSP) Inhibitors. 9. Discovery of (2S)-4-(2,5-Difluorophenyl)-N-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2- (hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (MK-0731) for the Treatment of Taxane-Refractory Cancer. J Med Chem. 2008 Jun 25;. PMID:18578472 doi:10.1021/jm800386y

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/3cjo"

@@ Line 5: / Line 5: @@
 </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=K30:(2S)-4-(2,5-DIFLUOROPHENYL)-N-[(3R,4S)-3-FLUORO-1-METHYLPIPERIDIN-4-YL]-2-(HYDROXYMETHYL)-N-METHYL-2-PHENYL-2,5-DIHYDRO-1H-PYRROLE-1-CARBOXAMIDE'>K30</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></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 Homo sapiens])</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=3cjo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3cjo OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3cjo RCSB], [http://www.ebi.ac.uk/pdbsum/3cjo 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=3cjo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3cjo OCA], [http://pdbe.org/3cjo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3cjo RCSB], [http://www.ebi.ac.uk/pdbsum/3cjo PDBsum]</span></td></tr>
 </table>
 == Disease ==
@@ Line 19: / Line 19: @@
     <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=3cjo ConSurf].
 <div style="clear:both"></div>
 <div style="background-color:#fffaf0;">
@@ Line 29: / Line 29: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 3cjo" style="background-color:#fffaf0;"></div>
 ==See Also==

3cjo

From Proteopedia

Revision as of 11:24, 8 February 2016

Crystal structure of KSP in complex with inhibitor 30

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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