4a5y

From Proteopedia

(Difference between revisions)

Revision as of 06:31, 20 May 2015

Intermediate state of human kinesin Eg5 in complex with Ispinesib

Structural highlights

4a5y 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:	2fky, 2x7c, 2xae, 1q0b, 2x2r, 2fl6, 2uym, 4a28, 2x7d, 2x7e, 1ii6, 4a51, 2uyi, 4a50, 4a1z, 2wog, 2g1q, 2gm1, 1yrs, 1x88, 2fl2
Resources:	FirstGlance, OCA, 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]

Publication Abstract from PubMed

Kinesins comprise a superfamily of molecular motors that drive a wide variety of cellular physiologies, from cytoplasmic transport to formation of the bipolar spindle in mitosis. These differing roles are reflected in corresponding polymorphisms in key kinesin structural elements. One of these is a unique loop and stem motif found in all kinesins and referred to as loop 5 (L5). This loop is longest in the mitotic kinesin Eg5 and is the target for a number of small molecule inhibitors, including ispinesib, which is being used in clinical trials in patients with cancer. In this study, we have used x-ray crystallography to identify a new structure of an Eg5-ispinesib complex and have combined this with transient state kinetics to identify a plausible sequence of conformational changes that occur in response to ispinesib binding. Our results demonstrate that ispinesib-induced structural changes in L5 from Eg5 lead to subsequent changes in the conformation of the switch II loop and helix and in the neck linker. We conclude that L5 in Eg5 simultaneously regulates the structure of both the ATP binding site and the motor's mechanical elements that generate force.

"Snapshots" of ispinesib-induced conformational changes in the mitotic kinesin Eg5.,Kaan HY, Major J, Tkocz K, Kozielski F, Rosenfeld SS J Biol Chem. 2013 Jun 21;288(25):18588-98. doi: 10.1074/jbc.M113.462648. Epub, 2013 May 8. PMID:23658017^[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
↑ Kaan HY, Major J, Tkocz K, Kozielski F, Rosenfeld SS. "Snapshots" of ispinesib-induced conformational changes in the mitotic kinesin Eg5. J Biol Chem. 2013 Jun 21;288(25):18588-98. doi: 10.1074/jbc.M113.462648. Epub, 2013 May 8. PMID:23658017 doi:http://dx.doi.org/10.1074/jbc.M113.462648

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/4a5y"

Categories: Human | Kaan, H Y.K | Kozielski, F | Mitosis | Motor protein

@@ Line 2: / Line 2: @@
 <StructureSection load='4a5y' size='340' side='right' caption='[[4a5y]], [[Resolution|resolution]] 2.45&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4a5y]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4A5Y OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4A5Y FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4a5y]] is a 3 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=4A5Y OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4A5Y 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=G7X:ISPINESIB+MESILATE'>G7X</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2fky|2fky]], [[2x7c|2x7c]], [[2xae|2xae]], [[1q0b|1q0b]], [[2x2r|2x2r]], [[2fl6|2fl6]], [[2uym|2uym]], [[4a28|4a28]], [[2x7d|2x7d]], [[2x7e|2x7e]], [[1ii6|1ii6]], [[4a51|4a51]], [[2uyi|2uyi]], [[4a50|4a50]], [[4a1z|4a1z]], [[2wog|2wog]], [[2g1q|2g1q]], [[2gm1|2gm1]], [[1yrs|1yrs]], [[1x88|1x88]], [[2fl2|2fl2]]</td></tr>
@@ Line 11: / Line 11: @@
 == 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>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Kinesins comprise a superfamily of molecular motors that drive a wide variety of cellular physiologies, from cytoplasmic transport to formation of the bipolar spindle in mitosis. These differing roles are reflected in corresponding polymorphisms in key kinesin structural elements. One of these is a unique loop and stem motif found in all kinesins and referred to as loop 5 (L5). This loop is longest in the mitotic kinesin Eg5 and is the target for a number of small molecule inhibitors, including ispinesib, which is being used in clinical trials in patients with cancer. In this study, we have used x-ray crystallography to identify a new structure of an Eg5-ispinesib complex and have combined this with transient state kinetics to identify a plausible sequence of conformational changes that occur in response to ispinesib binding. Our results demonstrate that ispinesib-induced structural changes in L5 from Eg5 lead to subsequent changes in the conformation of the switch II loop and helix and in the neck linker. We conclude that L5 in Eg5 simultaneously regulates the structure of both the ATP binding site and the motor's mechanical elements that generate force.
+"Snapshots" of ispinesib-induced conformational changes in the mitotic kinesin Eg5.,Kaan HY, Major J, Tkocz K, Kozielski F, Rosenfeld SS J Biol Chem. 2013 Jun 21;288(25):18588-98. doi: 10.1074/jbc.M113.462648. Epub, 2013 May 8. PMID:23658017<ref>PMID:23658017</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
 ==See Also==
@@ Line 18: / Line 26: @@
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Kaan, H Y.K]]
 [[Category: Kozielski, F]]
 [[Category: Mitosis]]
 [[Category: Motor protein]]

4a5y

From Proteopedia

Revision as of 06:31, 20 May 2015

Intermediate state of human kinesin Eg5 in complex with Ispinesib

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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