View source for 5hs3


==Human thymidylate synthase complexed with dUMP and 3-amino-2-benzoyl-4-methylthieno[2,3-b]pyridin-6-ol==
<StructureSection load='5hs3' size='340' side='right'caption='[[5hs3]], [[Resolution|resolution]] 3.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5hs3]] is a 6 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=5HS3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5HS3 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]] 3.103&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=KI3:3-AMINO-2-BENZOYL-4-METHYLTHIENO[2,3-B]PYRIDIN-6-OL'>KI3</scene>, <scene name='pdbligand=UMP:2-DEOXYURIDINE+5-MONOPHOSPHATE'>UMP</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=5hs3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hs3 OCA], [https://pdbe.org/5hs3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5hs3 RCSB], [https://www.ebi.ac.uk/pdbsum/5hs3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5hs3 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/TYSY_HUMAN TYSY_HUMAN] Contributes to the de novo mitochondrial thymidylate biosynthesis pathway.<ref>PMID:21876188</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Target engagement is a critical factor for therapeutic efficacy. Assessment of compound binding to native target proteins in live cells is therefore highly desirable in all stages of drug discovery. We report here the first compound library screen based on biophysical measurements of intracellular target binding, exemplified by human thymidylate synthase (TS). The screen selected accurately for all the tested known drugs acting on TS. We also identified TS inhibitors with novel chemistry and marketed drugs that were not previously known to target TS, including the DNA methyltransferase inhibitor decitabine. By following the cellular uptake and enzymatic conversion of known drugs we correlated the appearance of active metabolites over time with intracellular target engagement. These data distinguished a much slower activation of 5-fluorouracil when compared with nucleoside-based drugs. The approach establishes efficient means to associate drug uptake and activation with target binding during drug discovery.

CETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil.,Almqvist H, Axelsson H, Jafari R, Dan C, Mateus A, Haraldsson M, Larsson A, Martinez Molina D, Artursson P, Lundback T, Nordlund P Nat Commun. 2016 Mar 24;7:11040. doi: 10.1038/ncomms11040. PMID:27010513<ref>PMID:27010513</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5hs3" style="background-color:#fffaf0;"></div>

==See Also==
*[[Thymidylate synthase 3D structures|Thymidylate synthase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Almqvist H]]
[[Category: Artursson P]]
[[Category: Axelsson H]]
[[Category: Chen D]]
[[Category: Haraldsson M]]
[[Category: Jafari R]]
[[Category: Larsson A]]
[[Category: Lundback T]]
[[Category: Mateus A]]
[[Category: Molina DM]]
[[Category: Nordlund P]]