| Structural highlights
4aqv is a 3 chain structure with sequence from Bos taurus and Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , |
| Related: | 1ii6, 1jff, 1q0b, 1sa0, 1sa1, 1tvk, 1x88, 1yrs, 1z2b, 2fky, 2fl2, 2fl6, 2g1q, 2gm1, 2uyi, 2uym, 2wbe, 2wog, 2x2r, 2x7c, 2x7d, 2x7e, 2xae, 2xrp, 4a1z, 4a28, 4a50, 4a51, 4a5y, 4ap0, 4aqw, 4as7, 4atu, 4atx, 4b7b, 4bbg |
| 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
[TBA1D_BOVIN] Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain (By similarity). [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] [TBB2B_BOVIN] Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain (By similarity).
Publication Abstract from PubMed
Kinesin5 is required for forming the bipolar spindle during mitosis. Its motor domain, which contains nucleotide and microtubule binding sites and mechanical elements to generate force, has evolved distinct properties for its spindle based functions. In this study, we report subnanometer resolution cryoelectron microscopy reconstructions of microtubule bound human kinesin5 before and after nucleotide binding and combine this information with studies of the kinetics of nucleotide induced neck linker and cover strand movement. These studies reveal coupled, nucleotide dependent conformational changes that explain many of this motor's properties. We find that ATP binding induces a ratchet-like docking of the neck linker, and simultaneous, parallel docking of the amino-terminal cover strand. Loop L5-the binding site for allosteric inhibitors of kinesin5-also undergoes a dramatic reorientation when ATP binds, suggesting that it is directly involved in controlling nucleotide binding. Our structures indicate that allosteric inhibitors of human kinesin5, which are being developed as anti cancer therapeutics, bind to a motor conformation that occurs in the course of normal function. However, due to evolutionarily defined sequence variations in L5, this conformation is not adopted by invertebrate kinesin5s, explaining their resistance to drug inhibition. Together, our data reveal the precision with which the molecular mechanism of kinesin5 motors has evolved for force generation.
THE STRUCTURAL BASIS OF FORCE GENERATION BY THE MITOTIC MOTOR KINESIN-5.,Goulet A, Behnke-Parks WM, Sindelar CV, Major J, Rosenfeld SS, Moores C J Biol Chem. 2012 Nov 7. PMID:23135273[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
- ↑ Goulet A, Behnke-Parks WM, Sindelar CV, Major J, Rosenfeld SS, Moores C. THE STRUCTURAL BASIS OF FORCE GENERATION BY THE MITOTIC MOTOR KINESIN-5. J Biol Chem. 2012 Nov 7. PMID:23135273 doi:http://dx.doi.org/10.1074/jbc.M112.404228
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