3RSR

Crystal Structure of 5-NITP Inhibition of Yeast Ribonucleotide Reductase

Summary for 3RSR

• Entry DOI: 10.2210/pdb3rsr/pdb
• Related: 2CVS 2CVU 2CVV 2CVW 2CVX 2CVY
• Descriptor: Ribonucleoside-diphosphate reductase large chain 1, MAGNESIUM ION, 1-{2-DEOXY-5-O-[(R)-HYDROXY{[(R)-HYDROXY(PHOSPHONOOXY)PHOSPHORYL]OXY}PHOSPHORYL]-BETA-D-ERYTHRO-PENTOFURANOSYL}-5-NITRO -1H-INDOLE, ... (4 entities in total)
• Functional Keywords: 10-stranded alpha/beta barrel, nucleotide reduction, oxidized, oxidoreductase
• Biological source: Saccharomyces cerevisiae (yeast)
• Cellular location: Cytoplasm: P21524
• Total number of polymer chains: 1
• Total formula weight: 100215.49

Authors

Wan, Q.,Mohammed, F.,Jha, S.,Motea, E.,Berdis, A.,Dealwis, C.G. (deposition date: 2011-05-02, release date: 2012-11-14, Last modification date: 2024-11-06)

Primary citation

Ahmad, M.F.,Wan, Q.,Jha, S.,Motea, E.,Berdis, A.,Dealwis, C.
Evaluating the therapeutic potential of a non-natural nucleotide that inhibits human ribonucleotide reductase.
Mol.Cancer Ther., 11:2077-2086, 2012

PubMed Abstract: Human ribonucleotide reductase (hRR) is the key enzyme involved in de novo dNTP synthesis and thus represents an important therapeutic target against hyperproliferative diseases, most notably cancer. The purpose of this study was to evaluate the ability of non-natural indolyl-2'-deoxynucleoside triphosphates to inhibit the activity of hRR. The structural similarities of these analogues with dATP predicted that they would inhibit hRR activity by binding to its allosteric sites. In silico analysis and in vitro characterization identified one particular analogue designated as 5-nitro-indolyl-2'-deoxyribose triphosphate (5-NITP) that inhibits hRR. 5-NITP binding to hRR was determined by isothermal titration calorimetry. X-ray crystal structure of 5-NITP bound to RR1 was determined. Cell-based studies showed the anti-cancer effects of the corresponding non-natural nucleoside against leukemia cells. 5-NITP binds to hRR with micromolar affinity. Binding does not induce hexamerization of hRR1 like dATP, the native allosteric inhibitor of hRR that binds with high affinity to the A-site. The X-ray crystal structure of Saccharomyces cerevisiae RR1-5-NITP (ScRR1-5-NITP) complex determined to 2.3 Å resolution shows that 5-NITP does not bind to the A-site but rather at the S-site. Regardless, 5-nitro-indolyl-2'-deoxynucleoside (5-NIdR) produces cytostatic and cytotoxic effects against human leukemia cells by altering cell-cycle progression. Our studies provide useful insights toward developing new inhibitors with improved potency and efficacy against hRR.

PubMed: 22933704
DOI: 10.1158/1535-7163.MCT-12-0199

Experimental method

X-RAY DIFFRACTION (2.3 Å)