View source for 5tus


==Potent competitive inhibition of human ribonucleotide reductase by a novel non-nucleoside small molecule==
<StructureSection load='5tus' size='340' side='right'caption='[[5tus]], [[Resolution|resolution]] 2.66&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5tus]] is a 2 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=5TUS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TUS 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]] 2.66&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7LL:2-hydroxy-N-[(Z)-(2-hydroxynaphthalen-1-yl)methylidene]benzohydrazide'>7LL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=TTP:THYMIDINE-5-TRIPHOSPHATE'>TTP</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=5tus FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tus OCA], [https://pdbe.org/5tus PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tus RCSB], [https://www.ebi.ac.uk/pdbsum/5tus PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tus ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/RIR1_HUMAN RIR1_HUMAN] Provides the precursors necessary for DNA synthesis. Catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Human ribonucleotide reductase (hRR) is crucial for DNA replication and maintenance of a balanced dNTP pool, and is an established cancer target. Nucleoside analogs such as gemcitabine diphosphate and clofarabine nucleotides target the large subunit (hRRM1) of hRR. These drugs have a poor therapeutic index due to toxicity caused by additional effects, including DNA chain termination. The discovery of nonnucleoside, reversible, small-molecule inhibitors with greater specificity against hRRM1 is a key step in the development of more effective treatments for cancer. Here, we report the identification and characterization of a unique nonnucleoside small-molecule hRR inhibitor, naphthyl salicylic acyl hydrazone (NSAH), using virtual screening, binding affinity, inhibition, and cell toxicity assays. NSAH binds to hRRM1 with an apparent dissociation constant of 37 microM, and steady-state kinetics reveal a competitive mode of inhibition. A 2.66-A resolution crystal structure of NSAH in complex with hRRM1 demonstrates that NSAH functions by binding at the catalytic site (C-site) where it makes both common and unique contacts with the enzyme compared with NDP substrates. Importantly, the IC50 for NSAH is within twofold of gemcitabine for growth inhibition of multiple cancer cell lines, while demonstrating little cytotoxicity against normal mobilized peripheral blood progenitor cells. NSAH depresses dGTP and dATP levels in the dNTP pool causing S-phase arrest, providing evidence for RR inhibition in cells. This report of a nonnucleoside reversible inhibitor binding at the catalytic site of hRRM1 provides a starting point for the design of a unique class of hRR inhibitors.

Potent competitive inhibition of human ribonucleotide reductase by a nonnucleoside small molecule.,Ahmad MF, Alam I, Huff SE, Pink J, Flanagan SA, Shewach D, Misko TA, Oleinick NL, Harte WE, Viswanathan R, Harris ME, Dealwis CG Proc Natl Acad Sci U S A. 2017 Aug 1;114(31):8241-8246. doi:, 10.1073/pnas.1620220114. Epub 2017 Jul 17. PMID:28716944<ref>PMID:28716944</ref>

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

==See Also==
*[[Ribonucleotide reductase 3D structures|Ribonucleotide reductase 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Alam I]]
[[Category: Dealwis CG]]
[[Category: Mohammed FA]]