View source for 4qtc


==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=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4qtc]] 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=4QTC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4QTC FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.4&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=38Z:(3R)-1-(2-OXO-2-{4-[4-(PYRIMIDIN-2-YL)PHENYL]PIPERAZIN-1-YL}ETHYL)-N-[3-(PYRIDIN-4-YL)-2H-INDAZOL-5-YL]PYRROLIDINE-3-CARBOXAMIDE'>38Z</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</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=4qtc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qtc OCA], [https://pdbe.org/4qtc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4qtc RCSB], [https://www.ebi.ac.uk/pdbsum/4qtc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4qtc ProSAT]</span></td></tr>
</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 ==
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<ref>PMID:25195011</ref>

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 3D structures|Serine/threonine protein kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Arrowsmith CH]]
[[Category: Bountra C]]
[[Category: Chaikuad A]]
[[Category: Edwards AM]]
[[Category: Knapp S]]
[[Category: Von Delft F]]