| Structural highlights
2wog is a 3 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: | 1ii6, 2fky, 2uyi, 1q0b, 2g1q, 2fl6, 2gm1, 1yrs, 2uym, 1x88, 2fl2 |
| 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
Human kinesin Eg5 plays an essential role in mitosis by separating duplicated centrosomes and establishing the bipolar spindle. Eg5 is an interesting drug target for the development of cancer chemotherapy, with seven inhibitors already in clinical trials. In the present paper, we report the crystal structure of the Eg5 motor domain complexed with a potent antimitotic inhibitor STLC (S-trityl-L-cysteine) to 2.0 A (1 A=0.1 nm) resolution. The Eg5-STLC complex crystallizes in space group P3(2) with three molecules per asymmetric unit. Two of the molecules reveal the final inhibitor-bound state of Eg5, whereby loop L5 has swung downwards to close the inhibitor-binding pocket, helix alpha4 has rotated by approx. 15 degrees and the neck-linker has adopted a docked conformation. The third molecule, however, revealed an unprecedented intermediate state, whereby local changes at the inhibitor-binding pocket have not propagated to structural changes at the switch II cluster and neck-linker. This provides structural evidence for the sequence of drug-induced conformational changes.
An allosteric transition trapped in an intermediate state of a new kinesin-inhibitor complex.,Kaan HY, Ulaganathan V, Hackney DD, Kozielski F Biochem J. 2009 Dec 14;425(1):55-60. PMID:19793049[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Kaan HY, Ulaganathan V, Hackney DD, Kozielski F. An allosteric transition trapped in an intermediate state of a new kinesin-inhibitor complex. Biochem J. 2009 Dec 14;425(1):55-60. PMID:19793049 doi:10.1042/BJ20091207
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