4bi1: Difference between revisions

Latest revision as of 11:51, 20 December 2023

Scaffold Focused Virtual Screening: Prospective Application to the Discovery of TTK Inhibitor

Structural highlights

4bi1 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 2.7Å
Ligands:	7PE, EDO, ZO6
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

TTK_HUMAN Phosphorylates proteins on serine, threonine, and tyrosine. Probably associated with cell proliferation. Essential for chromosome alignment by enhancing AURKB activity (via direct CDCA8 phosphorylation) at the centromere, and for the mitotic checkpoint.^[1]

Publication Abstract from PubMed

We describe and apply a scaffold-focused virtual screen based upon scaffold trees to the mitotic kinase TTK (MPS1). Using level 1 of the scaffold tree, we perform both 2D and 3D similarity searches between a query scaffold and a level 1 scaffold library derived from a 2 million compound library; 98 compounds from 27 unique top-ranked level 1 scaffolds are selected for biochemical screening. We show that this scaffold-focused virtual screen prospectively identifies eight confirmed active compounds that are structurally differentiated from the query compound. In comparison, 100 compounds were selected for biochemical screening using a virtual screen based upon whole molecule similarity resulting in 12 confirmed active compounds that are structurally similar to the query compound. We elucidated the binding mode for four of the eight confirmed scaffold hops to TTK by determining their protein-ligand crystal structures; each represents a ligand-efficient scaffold for inhibitor design.

Scaffold-Focused Virtual Screening: Prospective Application to the Discovery of TTK Inhibitors.,Langdon SR, Westwood IM, van Montfort RL, Brown N, Blagg J J Chem Inf Model. 2013 May 24;53(5):1100-12. doi: 10.1021/ci400100c. Epub 2013, May 14. PMID:23672464^[2]

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

References

↑ Jelluma N, Brenkman AB, van den Broek NJ, Cruijsen CW, van Osch MH, Lens SM, Medema RH, Kops GJ. Mps1 phosphorylates Borealin to control Aurora B activity and chromosome alignment. Cell. 2008 Jan 25;132(2):233-46. doi: 10.1016/j.cell.2007.11.046. PMID:18243099 doi:10.1016/j.cell.2007.11.046
↑ Langdon SR, Westwood IM, van Montfort RL, Brown N, Blagg J. Scaffold-Focused Virtual Screening: Prospective Application to the Discovery of TTK Inhibitors. J Chem Inf Model. 2013 May 24;53(5):1100-12. doi: 10.1021/ci400100c. Epub 2013, May 14. PMID:23672464 doi:10.1021/ci400100c

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Jelluma N, Brenkman AB, van den Broek NJ, Cruijsen CW, van Osch MH, Lens SM, Medema RH, Kops GJ. Mps1 phosphorylates Borealin to control Aurora B activity and chromosome alignment. Cell. 2008 Jan 25;132(2):233-46. doi: 10.1016/j.cell.2007.11.046. PMID:18243099 doi:10.1016/j.cell.2007.11.046

[2] Langdon SR, Westwood IM, van Montfort RL, Brown N, Blagg J. Scaffold-Focused Virtual Screening: Prospective Application to the Discovery of TTK Inhibitors. J Chem Inf Model. 2013 May 24;53(5):1100-12. doi: 10.1021/ci400100c. Epub 2013, May 14. PMID:23672464 doi:10.1021/ci400100c

[1]

[2]

@@ Line 3: / Line 3: @@
 <StructureSection load='4bi1' size='340' side='right'caption='[[4bi1]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4bi1]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BI1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BI1 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4bi1]] 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=4BI1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BI1 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7PE:2-(2-(2-(2-(2-(2-ETHOXYETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHANOL'>7PE</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=ZO6:THIENO[3,2-C][2,6]NAPHTHYRIDINE'>ZO6</scene></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]] 2.7&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[4bhz|4bhz]], [[4bi0|4bi0]], [[4bi2|4bi2]]</div></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7PE:2-(2-(2-(2-(2-(2-ETHOXYETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHANOL'>7PE</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=ZO6:THIENO[3,2-C][2,6]NAPHTHYRIDINE'>ZO6</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Dual-specificity_kinase Dual-specificity kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.12.1 2.7.12.1] </span></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=4bi1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bi1 OCA], [https://pdbe.org/4bi1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bi1 RCSB], [https://www.ebi.ac.uk/pdbsum/4bi1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bi1 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/TTK_HUMAN TTK_HUMAN]] Phosphorylates proteins on serine, threonine, and tyrosine. Probably associated with cell proliferation. Essential for chromosome alignment by enhancing AURKB activity (via direct CDCA8 phosphorylation) at the centromere, and for the mitotic checkpoint.<ref>PMID:18243099</ref>
+[https://www.uniprot.org/uniprot/TTK_HUMAN TTK_HUMAN] Phosphorylates proteins on serine, threonine, and tyrosine. Probably associated with cell proliferation. Essential for chromosome alignment by enhancing AURKB activity (via direct CDCA8 phosphorylation) at the centromere, and for the mitotic checkpoint.<ref>PMID:18243099</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 27: / Line 26: @@
 __TOC__
 </StructureSection>
-[[Category: Dual-specificity kinase]]
+[[Category: Homo sapiens]]
-[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Blagg, J]]
+[[Category: Blagg J]]
-[[Category: Brown, N]]
+[[Category: Brown N]]
-[[Category: Langdon, S R]]
+[[Category: Langdon SR]]
-[[Category: Montfort, R L.M van]]
+[[Category: Westwood IM]]
-[[Category: Westwood, I M]]
+[[Category: Van Montfort RLM]]
-[[Category: Mitosis]]
-[[Category: Protein kinase]]
-[[Category: Transferase]]

4bi1: Difference between revisions

Latest revision as of 11:51, 20 December 2023

Scaffold Focused Virtual Screening: Prospective Application to the Discovery of TTK Inhibitor

Structural highlights

Function

Publication Abstract from PubMed

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References

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