View source for 7sql


==Crystal structure of human uridine-cytidine kinase 2 complexed with a weak small molecule inhibitor==
<StructureSection load='7sql' size='340' side='right'caption='[[7sql]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7sql]] is a 4 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=7SQL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7SQL 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]] 2.4&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AQX:N-(4-bromophenyl)-2-{[1-(4-fluorophenyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]sulfanyl}acetamide'>AQX</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</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=7sql FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7sql OCA], [https://pdbe.org/7sql PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7sql RCSB], [https://www.ebi.ac.uk/pdbsum/7sql PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7sql ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/UCK2_HUMAN UCK2_HUMAN] Phosphorylates uridine and cytidine to uridine monophosphate and cytidine monophosphate. Does not phosphorylate deoxyribonucleosides or purine ribonucleosides. Can use ATP or GTP as a phosphate donor. Can also phosphorylate cytidine and uridine nucleoside analogs such as 6-azauridine, 5-fluorouridine, 4-thiouridine, 5-bromouridine, N(4)-acetylcytidine, N(4)-benzoylcytidine, 5-fluorocytidine, 2-thiocytidine, 5-methylcytidine, and N(4)-anisoylcytidine.
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== Publication Abstract from PubMed ==
Pyrimidine nucleotide biosynthesis in humans is a promising chemotherapeutic target for infectious diseases caused by RNA viruses. Because mammalian cells derive pyrimidine ribonucleotides through a combination of de novo biosynthesis and salvage, combined inhibition of dihydroorotate dehydrogenase (DHODH; the first committed step in de novo pyrimidine nucleotide biosynthesis) and uridine/cytidine kinase 2 (UCK2; the first step in salvage of exogenous nucleosides) strongly attenuates viral replication in infected cells. However, while several pharmacologically promising inhibitors of human DHODH are known, to date there are no reports of medicinally viable leads against UCK2. Here, we use structure-based drug prototyping to identify two classes of promising leads that noncompetitively inhibit UCK2 activity. In the process, we have identified a hitherto unknown allosteric site at the intersubunit interface of this homotetrameric enzyme. By reducing the k(cat) of human UCK2 without altering its K(M), these new inhibitors have the potential to enable systematic dialing of the fractional inhibition of pyrimidine salvage to achieve the desired antiviral effect with minimal host toxicity.

Structure-Based Prototyping of Allosteric Inhibitors of Human Uridine/Cytidine Kinase 2 (UCK2).,Mashayekh S, Stunkard LM, Kienle M, Mathews II, Khosla C Biochemistry. 2022 Nov 1;61(21):2261-2266. doi: 10.1021/acs.biochem.2c00451. Epub , 2022 Oct 3. PMID:36190114<ref>PMID:36190114</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 7sql" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Khosla C]]
[[Category: Kienle M]]
[[Category: Mashayekh S]]
[[Category: Mathews II]]
[[Category: Stunkard LM]]