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6tiw

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Revision as of 06:30, 11 April 2020

Human kinesin-5 motor domain in the GSK state bound to microtubules (Conformation 2)

6tiw, resolution 1.09Å

Structural highlights

6tiw is a 3 chain structure with sequence from [1] and Sus scrofa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Experimental data:	Check to display Experimental Data
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] [TBA1B_PIG] 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. [TBB_PIG] 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.

Publication Abstract from PubMed

Kinesin-5 motors are vital mitotic spindle components, and disruption of their function perturbs cell division. We investigated the molecular mechanism of the human kinesin-5 inhibitor GSK-1, which allosterically promotes tight microtubule binding. GSK-1 inhibits monomeric human kinesin-5 ATPase and microtubule gliding activities, and promotes the motor's microtubule stabilization activity. Using cryoelectron microscopy, we determined the 3D structure of the microtubule-bound motor-GSK-1 at 3.8 A overall resolution. The structure reveals that GSK-1 stabilizes the microtubule binding surface of the motor in an ATP-like conformation, while destabilizing regions of the motor around the empty nucleotide binding pocket. Density corresponding to GSK-1 is located between helix-alpha4 and helix-alpha6 in the motor domain at its interface with the microtubule. Using a combination of difference mapping and protein-ligand docking, we characterized the kinesin-5-GSK-1 interaction and further validated this binding site using mutagenesis. This work opens up new avenues of investigation of kinesin inhibition and spindle perturbation.

Structure of Microtubule-Trapped Human Kinesin-5 and Its Mechanism of Inhibition Revealed Using Cryoelectron Microscopy.,Pena A, Sweeney A, Cook AD, Topf M, Moores CA Structure. 2020 Feb 11. pii: S0969-2126(20)30040-X. doi:, 10.1016/j.str.2020.01.013. PMID:32084356^[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
↑ Pena A, Sweeney A, Cook AD, Topf M, Moores CA. Structure of Microtubule-Trapped Human Kinesin-5 and Its Mechanism of Inhibition Revealed Using Cryoelectron Microscopy. Structure. 2020 Feb 11. pii: S0969-2126(20)30040-X. doi:, 10.1016/j.str.2020.01.013. PMID:32084356 doi:http://dx.doi.org/10.1016/j.str.2020.01.013

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

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

@@ Line 3: / Line 3: @@
 <SX load='6tiw' size='340' side='right' viewer='molstar' caption='[[6tiw]], [[Resolution|resolution]] 1.09&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6tiw]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/ ] and [http://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TIW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6TIW FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6tiw]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/ ] and [http://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TIW OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6TIW FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=G2P:PHOSPHOMETHYLPHOSPHONIC+ACID+GUANYLATE+ESTER'>G2P</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=MZK:6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1~{H}-quinolin-2-one'>MZK</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=G2P:PHOSPHOMETHYLPHOSPHONIC+ACID+GUANYLATE+ESTER'>G2P</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=MZK:6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1~{H}-quinolin-2-one'>MZK</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=6tiw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tiw OCA], [http://pdbe.org/6tiw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6tiw RCSB], [http://www.ebi.ac.uk/pdbsum/6tiw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6tiw ProSAT]</span></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=6tiw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tiw OCA], [http://pdbe.org/6tiw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6tiw RCSB], [http://www.ebi.ac.uk/pdbsum/6tiw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6tiw ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 20: / Line 20: @@
 </div>
 <div class="pdbe-citations 6tiw" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Tubulin 3D Structures|Tubulin 3D Structures]]
 == References ==
 <references/>

6tiw

From Proteopedia

Revision as of 06:30, 11 April 2020

Human kinesin-5 motor domain in the GSK state bound to microtubules (Conformation 2)

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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