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4qtc

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Revision as of 09:08, 5 August 2016

Structure of human haspin (GSG2) in complex with SCH772984 revealing the first type-I binding mode

Structural highlights

4qtc is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	4qta, 4qtb, 4qtd, 4qte
Activity:	Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
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

Activation of the ERK pathway is a hallmark of cancer, and targeting of upstream signaling partners led to the development of approved drugs. Recently, SCH772984 has been shown to be a selective and potent ERK1/2 inhibitor. Here we report the structural mechanism for its remarkable selectivity. In ERK1/2, SCH772984 induces a so-far-unknown binding pocket that accommodates the piperazine-phenyl-pyrimidine decoration. This new binding pocket was created by an inactive conformation of the phosphate-binding loop and an outward tilt of helix alphaC. In contrast, structure determination of SCH772984 with the off-target haspin and JNK1 revealed two canonical but distinct type I binding modes. Notably, the new binding mode with ERK1/2 was associated with slow binding kinetics in vitro as well as in cell-based assay systems. The described binding mode of SCH772984 with ERK1/2 enables the design of a new type of specific kinase inhibitors with prolonged on-target activity.

A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics.,Chaikuad A, M C Tacconi E, Zimmer J, Liang Y, Gray NS, Tarsounas M, Knapp S Nat Chem Biol. 2014 Oct;10(10):853-60. doi: 10.1038/nchembio.1629. Epub 2014 Sep , 7. PMID:25195011^[6]

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

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
↑ Chaikuad A, M C Tacconi E, Zimmer J, Liang Y, Gray NS, Tarsounas M, Knapp S. A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics. Nat Chem Biol. 2014 Oct;10(10):853-60. doi: 10.1038/nchembio.1629. Epub 2014 Sep , 7. PMID:25195011 doi:http://dx.doi.org/10.1038/nchembio.1629

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/4qtc"

@@ Line 1: / Line 1: @@
 ==Structure of human haspin (GSG2) in complex with SCH772984 revealing the first type-I binding mode==
 <StructureSection load='4qtc' size='340' side='right' caption='[[4qtc]], [[Resolution|resolution]] 1.40&Aring;' scene=''>
@@ Line 6: / Line 7: @@
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4qta|4qta]], [[4qtb|4qtb]], [[4qtd|4qtd]], [[4qte|4qte]]</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=4qtc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qtc OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4qtc RCSB], [http://www.ebi.ac.uk/pdbsum/4qtc PDBsum]</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=4qtc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qtc OCA], [http://pdbe.org/4qtc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4qtc RCSB], [http://www.ebi.ac.uk/pdbsum/4qtc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4qtc ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 19: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4qtc" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Serine/threonine protein kinase|Serine/threonine protein kinase]]
 == References ==
 <references/>

4qtc

From Proteopedia

Revision as of 09:08, 5 August 2016

Structure of human haspin (GSG2) in complex with SCH772984 revealing the first type-I binding mode

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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