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| | ==Crystal structure of haspin (GSG2) in complex with bisubstrate inhibitor ARC-3372== | | ==Crystal structure of haspin (GSG2) in complex with bisubstrate inhibitor ARC-3372== |
| - | <StructureSection load='5htc' size='340' side='right' caption='[[5htc]], [[Resolution|resolution]] 1.50Å' scene=''> | + | <StructureSection load='5htc' size='340' side='right'caption='[[5htc]], [[Resolution|resolution]] 1.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5htc]] is a 2 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=5HTC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5HTC FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5htc]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HTC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5HTC FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=66M:(2R)-2-{[6-({[(2S,3S,4R,5R)-5-(6-AMINO-9H-PURIN-9-YL)-3,4-DIHYDROXYTETRAHYDROFURAN-2-YL]CARBONYL}AMINO)HEXANOYL]AMINO}BUTANEDIOIC+ACID+(NON-PREFERRED+NAME)'>66M</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=66M:(2R)-2-{[6-({[(2S,3S,4R,5R)-5-(6-AMINO-9H-PURIN-9-YL)-3,4-DIHYDROXYTETRAHYDROFURAN-2-YL]CARBONYL}AMINO)HEXANOYL]AMINO}BUTANEDIOIC+ACID+(NON-PREFERRED+NAME)'>66M</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene></td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=66N:L-ALANINAMIDE'>66N</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=5htc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5htc OCA], [https://pdbe.org/5htc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5htc RCSB], [https://www.ebi.ac.uk/pdbsum/5htc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5htc ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GSG2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></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=5htc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5htc OCA], [http://pdbe.org/5htc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5htc RCSB], [http://www.ebi.ac.uk/pdbsum/5htc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5htc ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5htc" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5htc" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Non-specific serine/threonine protein kinase]] | + | [[Category: Large Structures]] |
| - | [[Category: Arrowsmith, C H]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Bountra, C]] | + | [[Category: Arrowsmith CH]] |
| - | [[Category: Chaikuad, A]] | + | [[Category: Bountra C]] |
| - | [[Category: Delft, F von]] | + | [[Category: Chaikuad A]] |
| - | [[Category: Edwards, A M]] | + | [[Category: Edwards AM]] |
| - | [[Category: Heroven, C]] | + | [[Category: Heroven C]] |
| - | [[Category: Kestav, K]] | + | [[Category: Kestav K]] |
| - | [[Category: Knapp, S]] | + | [[Category: Knapp S]] |
| - | [[Category: Lavogina, D]] | + | [[Category: Lavogina D]] |
| - | [[Category: Structural genomic]]
| + | [[Category: Uri A]] |
| - | [[Category: Uri, A]] | + | [[Category: Von Delft F]] |
| - | [[Category: Allosteric]] | + | |
| - | [[Category: Bisubstrate inhibitor]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Kinase]]
| + | |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| Structural highlights
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 is a mitotic protein kinase that is responsible for the phosphorylation of Thr3 of histone H3, thereby creating a recognition motif for docking of the chromosomal passenger complex that is crucial for the progression of cell division. Here, two high-resolution models of haspin with previously reported inhibitors consisting of an ATP analogue and a histone H3(1-7) peptide analogue are presented. The structures of the complexes confirm the bisubstrate character of the inhibitors by revealing the signature binding modes of the moieties targeting the ATP-binding site and the protein substrate-binding site of the kinase. This is the first structural model of a bisubstrate inhibitor targeting haspin. The presented structural data represent a model for the future development of more specific haspin inhibitors.
Co-crystal structures of the protein kinase haspin with bisubstrate inhibitors.,Lavogina D, Kestav K, Chaikuad A, Heroven C, Knapp S, Uri A Acta Crystallogr F Struct Biol Commun. 2016 May 1;72(Pt 5):339-45. doi:, 10.1107/S2053230X16004611. Epub 2016 Apr 22. PMID:27139824[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Lavogina D, Kestav K, Chaikuad A, Heroven C, Knapp S, Uri A. Co-crystal structures of the protein kinase haspin with bisubstrate inhibitors. Acta Crystallogr F Struct Biol Commun. 2016 May 1;72(Pt 5):339-45. doi:, 10.1107/S2053230X16004611. Epub 2016 Apr 22. PMID:27139824 doi:http://dx.doi.org/10.1107/S2053230X16004611
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