2xnp

From Proteopedia

(Difference between revisions)

Current revision

Structure of Nek2 bound to CCT244858

Structural highlights

2xnp is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.98Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

NEK2_HUMAN Protein kinase which is involved in the control of centrosome separation and bipolar spindle formation in mitotic cells and chromatin condensation in meiotic cells. Regulates centrosome separation (essential for the formation of bipolar spindles and high-fidelity chromosome separation) by phosphorylating centrosomal proteins such as CROCC, CEP250 and NINL, resulting in their displacement from the centrosomes. Regulates kinetochore microtubule attachment stability in mitosis via phosphorylation of NDC80. Involved in regulation of mitotic checkpoint protein complex via phosphorylation of CDC20 and MAD2L1. Plays an active role in chromatin condensation during the first meiotic division through phosphorylation of HMGA2. Phosphorylates: PPP1CC; SGOL1; NECAB3 and NPM1. Essential for localization of MAD2L1 to kinetochore and MAPK1 and NPM1 to the centrosome. Isoform 1 phosphorylates and activates NEK11 in G1/S-arrested cells. Isoform 2, which is not present in the nucleolus, does not.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] ^[11] ^[12] ^[13]

Publication Abstract from PubMed

We describe herein the structure-activity relationship (SAR) and cocrystal structures of a series of Nek2 inhibitors derived from the published polo-like kinase 1 (Plk1) inhibitor (R)-1. Our studies reveal a nonlinear SAR for Nek2 and our cocrystal structures show that compounds in this series bind to a DFG-out conformation of Nek2 without extending into the enlarged back pocket commonly found in this conformation. These observations were further investigated, and structure-based design led to Nek2 inhibitors derived from (R)-1 with more than a hundred-fold selectivity against Plk1.

Benzimidazole Inhibitors Induce a DFG-Out Conformation of Never in Mitosis Gene A-Related Kinase 2 (Nek2) without Binding to the Back Pocket and Reveal a Nonlinear Structure-Activity Relationship.,Solanki S, Innocenti P, Mas-Droux C, Boxall K, Barillari C, van Montfort RL, Aherne GW, Bayliss R, Hoelder S J Med Chem. 2011 Mar 24;54(6):1626-39. Epub 2011 Mar 2. PMID:21366329^[14]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Hames RS, Fry AM. Alternative splice variants of the human centrosome kinase Nek2 exhibit distinct patterns of expression in mitosis. Biochem J. 2002 Jan 1;361(Pt 1):77-85. PMID:11742531
↑ Lou Y, Yao J, Zereshki A, Dou Z, Ahmed K, Wang H, Hu J, Wang Y, Yao X. NEK2A interacts with MAD1 and possibly functions as a novel integrator of the spindle checkpoint signaling. J Biol Chem. 2004 May 7;279(19):20049-57. Epub 2004 Feb 20. PMID:14978040 doi:10.1074/jbc.M314205200
↑ Faragher AJ, Fry AM. Nek2A kinase stimulates centrosome disjunction and is required for formation of bipolar mitotic spindles. Mol Biol Cell. 2003 Jul;14(7):2876-89. Epub 2003 Apr 17. PMID:12857871 doi:10.1091/mbc.E03-02-0108
↑ Lou Y, Xie W, Zhang DF, Yao JH, Luo ZF, Wang YZ, Shi YY, Yao XB. Nek2A specifies the centrosomal localization of Erk2. Biochem Biophys Res Commun. 2004 Aug 20;321(2):495-501. PMID:15358203 doi:10.1016/j.bbrc.2004.06.171
↑ Yao J, Fu C, Ding X, Guo Z, Zenreski A, Chen Y, Ahmed K, Liao J, Dou Z, Yao X. Nek2A kinase regulates the localization of numatrin to centrosome in mitosis. FEBS Lett. 2004 Sep 24;575(1-3):112-8. PMID:15388344 doi:10.1016/j.febslet.2004.08.047
↑ Noguchi K, Fukazawa H, Murakami Y, Uehara Y. Nucleolar Nek11 is a novel target of Nek2A in G1/S-arrested cells. J Biol Chem. 2004 Jul 30;279(31):32716-27. Epub 2004 May 25. PMID:15161910 doi:10.1074/jbc.M404104200
↑ Mi J, Guo C, Brautigan DL, Larner JM. Protein phosphatase-1alpha regulates centrosome splitting through Nek2. Cancer Res. 2007 Feb 1;67(3):1082-9. PMID:17283141 doi:10.1158/0008-5472.CAN-06-3071
↑ Fu G, Ding X, Yuan K, Aikhionbare F, Yao J, Cai X, Jiang K, Yao X. Phosphorylation of human Sgo1 by NEK2A is essential for chromosome congression in mitosis. Cell Res. 2007 Jul;17(7):608-18. PMID:17621308 doi:10.1038/cr.2007.55
↑ Wu W, Baxter JE, Wattam SL, Hayward DG, Fardilha M, Knebel A, Ford EM, da Cruz e Silva EF, Fry AM. Alternative splicing controls nuclear translocation of the cell cycle-regulated Nek2 kinase. J Biol Chem. 2007 Sep 7;282(36):26431-40. Epub 2007 Jul 11. PMID:17626005 doi:10.1074/jbc.M704969200
↑ Bahmanyar S, Kaplan DD, Deluca JG, Giddings TH Jr, O'Toole ET, Winey M, Salmon ED, Casey PJ, Nelson WJ, Barth AI. beta-Catenin is a Nek2 substrate involved in centrosome separation. Genes Dev. 2008 Jan 1;22(1):91-105. Epub 2007 Dec 17. PMID:18086858 doi:10.1101/gad.1596308
↑ Du J, Cai X, Yao J, Ding X, Wu Q, Pei S, Jiang K, Zhang Y, Wang W, Shi Y, Lai Y, Shen J, Teng M, Huang H, Fei Q, Reddy ES, Zhu J, Jin C, Yao X. The mitotic checkpoint kinase NEK2A regulates kinetochore microtubule attachment stability. Oncogene. 2008 Jul 3;27(29):4107-14. doi: 10.1038/onc.2008.34. Epub 2008 Feb 25. PMID:18297113 doi:10.1038/onc.2008.34
↑ Liu Q, Hirohashi Y, Du X, Greene MI, Wang Q. Nek2 targets the mitotic checkpoint proteins Mad2 and Cdc20: a mechanism for aneuploidy in cancer. Exp Mol Pathol. 2010 Apr;88(2):225-33. doi: 10.1016/j.yexmp.2009.12.004. Epub, 2009 Dec 23. PMID:20034488 doi:10.1016/j.yexmp.2009.12.004
↑ Mardin BR, Lange C, Baxter JE, Hardy T, Scholz SR, Fry AM, Schiebel E. Components of the Hippo pathway cooperate with Nek2 kinase to regulate centrosome disjunction. Nat Cell Biol. 2010 Dec;12(12):1166-76. doi: 10.1038/ncb2120. Epub 2010 Nov 14. PMID:21076410 doi:10.1038/ncb2120
↑ Solanki S, Innocenti P, Mas-Droux C, Boxall K, Barillari C, van Montfort RL, Aherne GW, Bayliss R, Hoelder S. Benzimidazole Inhibitors Induce a DFG-Out Conformation of Never in Mitosis Gene A-Related Kinase 2 (Nek2) without Binding to the Back Pocket and Reveal a Nonlinear Structure-Activity Relationship. J Med Chem. 2011 Mar 24;54(6):1626-39. Epub 2011 Mar 2. PMID:21366329 doi:10.1021/jm1011726

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2xnp"

Categories: Homo sapiens | Large Structures | Bayliss R | Mas-Droux C

@@ Line 1: / Line 1: @@
-[[Image:2xnp.jpg|left|200px]]
-<!--
+==Structure of Nek2 bound to CCT244858==
-The line below this paragraph, containing "STRUCTURE_2xnp", creates the "Structure Box" on the page.
+<StructureSection load='2xnp' size='340' side='right'caption='[[2xnp]], [[Resolution|resolution]] 1.98&Aring;' scene=''>
-You may change the PDB parameter (which sets the PDB file loaded into the applet)
+== Structural highlights ==
-or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
+<table><tr><td colspan='2'>[[2xnp]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2XNP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2XNP FirstGlance]. <br>
-or leave the SCENE parameter empty for the default display.
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.98&#8491;</td></tr>
--->
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=WCX:4-{5-[(1-METHYLPIPERIDIN-4-YL)OXY]-1H-BENZIMIDAZOL-1-YL}-2-{(1R)-1-[2-(TRIFLUOROMETHYL)PHENYL]ETHOXY}BENZAMIDE'>WCX</scene></td></tr>
-{{STRUCTURE_2xnp|  PDB=2xnp  |  SCENE=  }}
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2xnp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xnp OCA], [https://pdbe.org/2xnp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2xnp RCSB], [https://www.ebi.ac.uk/pdbsum/2xnp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2xnp ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/NEK2_HUMAN NEK2_HUMAN] Protein kinase which is involved in the control of centrosome separation and bipolar spindle formation in mitotic cells and chromatin condensation in meiotic cells. Regulates centrosome separation (essential for the formation of bipolar spindles and high-fidelity chromosome separation) by phosphorylating centrosomal proteins such as CROCC, CEP250 and NINL, resulting in their displacement from the centrosomes. Regulates kinetochore microtubule attachment stability in mitosis via phosphorylation of NDC80. Involved in regulation of mitotic checkpoint protein complex via phosphorylation of CDC20 and MAD2L1. Plays an active role in chromatin condensation during the first meiotic division through phosphorylation of HMGA2. Phosphorylates: PPP1CC; SGOL1; NECAB3 and NPM1. Essential for localization of MAD2L1 to kinetochore and MAPK1 and NPM1 to the centrosome. Isoform 1 phosphorylates and activates NEK11 in G1/S-arrested cells. Isoform 2, which is not present in the nucleolus, does not.<ref>PMID:11742531</ref> <ref>PMID:14978040</ref> <ref>PMID:12857871</ref> <ref>PMID:15358203</ref> <ref>PMID:15388344</ref> <ref>PMID:15161910</ref> <ref>PMID:17283141</ref> <ref>PMID:17621308</ref> <ref>PMID:17626005</ref> <ref>PMID:18086858</ref> <ref>PMID:18297113</ref> <ref>PMID:20034488</ref> <ref>PMID:21076410</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+We describe herein the structure-activity relationship (SAR) and cocrystal structures of a series of Nek2 inhibitors derived from the published polo-like kinase 1 (Plk1) inhibitor (R)-1. Our studies reveal a nonlinear SAR for Nek2 and our cocrystal structures show that compounds in this series bind to a DFG-out conformation of Nek2 without extending into the enlarged back pocket commonly found in this conformation. These observations were further investigated, and structure-based design led to Nek2 inhibitors derived from (R)-1 with more than a hundred-fold selectivity against Plk1.
-===STRUCTURE OF NEK2 BOUND TO CCT244858===
+Benzimidazole Inhibitors Induce a DFG-Out Conformation of Never in Mitosis Gene A-Related Kinase 2 (Nek2) without Binding to the Back Pocket and Reveal a Nonlinear Structure-Activity Relationship.,Solanki S, Innocenti P, Mas-Droux C, Boxall K, Barillari C, van Montfort RL, Aherne GW, Bayliss R, Hoelder S J Med Chem. 2011 Mar 24;54(6):1626-39. Epub 2011 Mar 2. PMID:21366329<ref>PMID:21366329</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 2xnp" style="background-color:#fffaf0;"></div>
-<!--
+==See Also==
-The line below this paragraph, {{ABSTRACT_PUBMED_21366329}}, adds the Publication Abstract to the page
+*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]]
-(as it appears on PubMed at http://www.pubmed.gov), where 21366329 is the PubMed ID number.
+== References ==
--->
+<references/>
-{{ABSTRACT_PUBMED_21366329}}
+__TOC__
+</StructureSection>
-==About this Structure==
-[[2xnp]] is a 1 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=2XNP OCA].
-==Reference==
-<ref group="xtra">PMID:21366329</ref><references group="xtra"/>
 [[Category: Homo sapiens]]
-[[Category: Non-specific serine/threonine protein kinase]]
+[[Category: Large Structures]]
-[[Category: Bayliss, R.]]
+[[Category: Bayliss R]]
-[[Category: Mas-Droux, C.]]
+[[Category: Mas-Droux C]]

2xnp

From Proteopedia

Current revision

Structure of Nek2 bound to CCT244858

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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