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==Crystal structure of haspin in complex with ZW282 (compound 2a)==
==Crystal structure of haspin in complex with ZW282 (compound 2a)==
<StructureSection load='7ops' size='340' side='right'caption='[[7ops]]' scene=''>
<StructureSection load='7ops' size='340' side='right'caption='[[7ops]], [[Resolution|resolution]] 2.38&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7OPS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OPS FirstGlance]. <br>
<table><tr><td colspan='2'>[[7ops]] 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=7OPS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OPS FirstGlance]. <br>
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7ops FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ops OCA], [https://pdbe.org/7ops PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ops RCSB], [https://www.ebi.ac.uk/pdbsum/7ops PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ops ProSAT]</span></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.38&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=07C:2-methylsulfanyl-10-nitro-pyrido[3,4-g]quinazoline'>07C</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7ops FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ops OCA], [https://pdbe.org/7ops PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ops RCSB], [https://www.ebi.ac.uk/pdbsum/7ops PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ops ProSAT]</span></td></tr>
</table>
</table>
== Function ==
[https://www.uniprot.org/uniprot/HASP_HUMAN HASP_HUMAN] Serine/threonine-protein kinase that phosphorylates histone H3 at 'Ser-3' (H3T3ph) during mitosis. This positions and activates AURKB and other components of the chromosomal passenger complex (CPC) at centromeres to ensure proper chromatid cohesion, metaphase alignment and normal progression through the cell cycle.<ref>PMID:11228240</ref> <ref>PMID:15681610</ref> <ref>PMID:17084365</ref> <ref>PMID:20705812</ref> <ref>PMID:20929775</ref>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Haspin (haploid germ cell-specific nuclear protein kinase) offers a potential target for the development of new anticancer drugs. Thus, the identification of new inhibitors targeting this protein kinase is of high interest. However, Haspin inhibitors developed to date show a poor selectivity profile over other protein kinases of the human kinome. Here, we identified a new pyridoquinazoline based inhibitor (4), with excellent inhibitory activity and selectivity for Haspin (IC50 of 50 nM). We describe the structure-activity relationship study including the evaluation of this inhibitor on a large panel of 486 kinases as well as on immortalized or cancer cell lines. In addition, we determined the binding mode of analog 2a in complex with Haspin using X-ray crystallography.
Synthesis and biological evaluation of Haspin inhibitors: Kinase inhibitory potency and cellular activity.,Zeinyeh W, Esvan YJ, Josselin B, Defois M, Baratte B, Knapp S, Chaikuad A, Anizon F, Giraud F, Ruchaud S, Moreau P Eur J Med Chem. 2022 Apr 9;236:114369. doi: 10.1016/j.ejmech.2022.114369. PMID:35447555<ref>PMID:35447555</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7ops" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]]
*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Anizon F]]
[[Category: Anizon F]]
[[Category: Chaikuad A]]
[[Category: Chaikuad A]]
[[Category: Knapp S]]
[[Category: Knapp S]]

Latest revision as of 15:54, 1 February 2024

Crystal structure of haspin in complex with ZW282 (compound 2a)Crystal structure of haspin in complex with ZW282 (compound 2a)

Structural highlights

7ops 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 2.38Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

HASP_HUMAN Serine/threonine-protein kinase that phosphorylates histone H3 at 'Ser-3' (H3T3ph) during mitosis. This positions and activates AURKB and other components of the chromosomal passenger complex (CPC) at centromeres to ensure proper chromatid cohesion, metaphase alignment and normal progression through the cell cycle.[1] [2] [3] [4] [5]

Publication Abstract from PubMed

Haspin (haploid germ cell-specific nuclear protein kinase) offers a potential target for the development of new anticancer drugs. Thus, the identification of new inhibitors targeting this protein kinase is of high interest. However, Haspin inhibitors developed to date show a poor selectivity profile over other protein kinases of the human kinome. Here, we identified a new pyridoquinazoline based inhibitor (4), with excellent inhibitory activity and selectivity for Haspin (IC50 of 50 nM). We describe the structure-activity relationship study including the evaluation of this inhibitor on a large panel of 486 kinases as well as on immortalized or cancer cell lines. In addition, we determined the binding mode of analog 2a in complex with Haspin using X-ray crystallography.

Synthesis and biological evaluation of Haspin inhibitors: Kinase inhibitory potency and cellular activity.,Zeinyeh W, Esvan YJ, Josselin B, Defois M, Baratte B, Knapp S, Chaikuad A, Anizon F, Giraud F, Ruchaud S, Moreau P Eur J Med Chem. 2022 Apr 9;236:114369. doi: 10.1016/j.ejmech.2022.114369. PMID:35447555[6]

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

See Also

References

  1. ↑ Tanaka H, Iguchi N, Nakamura Y, Kohroki J, de Carvalho CE, Nishimune Y. Cloning and characterization of human haspin gene encoding haploid germ cell-specific nuclear protein kinase. Mol Hum Reprod. 2001 Mar;7(3):211-8. PMID:11228240
  2. ↑ Dai J, Sultan S, Taylor SS, Higgins JM. The kinase haspin is required for mitotic histone H3 Thr 3 phosphorylation and normal metaphase chromosome alignment. Genes Dev. 2005 Feb 15;19(4):472-88. Epub 2005 Jan 28. PMID:15681610 doi:gad.1267105
  3. ↑ Dai J, Sullivan BA, Higgins JM. Regulation of mitotic chromosome cohesion by Haspin and Aurora B. Dev Cell. 2006 Nov;11(5):741-50. PMID:17084365 doi:10.1016/j.devcel.2006.09.018
  4. ↑ Wang F, Dai J, Daum JR, Niedzialkowska E, Banerjee B, Stukenberg PT, Gorbsky GJ, Higgins JM. Histone H3 Thr-3 phosphorylation by Haspin positions Aurora B at centromeres in mitosis. Science. 2010 Oct 8;330(6001):231-5. doi: 10.1126/science.1189435. Epub 2010 Aug , 12. PMID:20705812 doi:10.1126/science.1189435
  5. ↑ Yamagishi Y, Honda T, Tanno Y, Watanabe Y. Two histone marks establish the inner centromere and chromosome bi-orientation. Science. 2010 Oct 8;330(6001):239-43. doi: 10.1126/science.1194498. PMID:20929775 doi:10.1126/science.1194498
  6. ↑ Zeinyeh W, Esvan YJ, Josselin B, Defois M, Baratte B, Knapp S, Chaikuad A, Anizon F, Giraud F, Ruchaud S, Moreau P. Synthesis and biological evaluation of Haspin inhibitors: Kinase inhibitory potency and cellular activity. Eur J Med Chem. 2022 Apr 9;236:114369. doi: 10.1016/j.ejmech.2022.114369. PMID:35447555 doi:http://dx.doi.org/10.1016/j.ejmech.2022.114369

7ops, resolution 2.38Å

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