Understanding the molecular interactions of different radical scavengers with ribonucleotide reductase M2 (hRRM2) domain: opening the gates and gaining access
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We employed a combination of molecular docking and dynamics to understand the interaction of three different radical scavengers (SB-HSC21, ABNM13 and trimidox) with ribonucleotide reductase M2 (hRRM2) domain. On the basis of the observed results, we can propose how these ligands interact with the enzyme, and cease the radical transfer step from the di-iron center to TYR176. All the ligands alter the electron density over TYR176, –OH group by forming an extremely stable H-bond with either –NHOH group, or with phenolic hydroxyl group of the ligands. This change in electronic density disrupts the water bridge between TYR176, –OH and the di-iron center, which stops the single electron transfer process from TYR176, –OH to iron. As a consequence the enzyme is inhibited. Another interesting observation that we are reporting is the two stage gate keeping mechanism of the RR active site tunnel. We describe these as the outer Gate-1 controlled by ARG330, and the inner Gate-2 controlled by SER263, PHE240, and PHE236. We also observed a dynamic conformational shift in these residues, the incoming ligands can go through, and interact with the underlying TYR176, –OH group. From the study we found the active—site of hRRM2 is extremely flexible and shows a significant induced fit.
KeywordsMolecular dynamics Ribonucleotide reductase (RR) Gate keeper residues Molecular docking
We thank University Grants Commission for providing necessary financial support for the current work. We also thank Mrs. Nibha Mishra and Dr. Venkatesan J for proofreading our manuscript.
- 12.Holland KP, Elford HL, Bracchi V, Annis CG, Schuster SM, Chakrabarti D (1998) Antimalarial activities of polyhydroxyphenyl and hydroxamic acid derivatives. Antimicrob Agents Chemother 42:2456Google Scholar
- 13.Yun D, Saleh L, García-Serres R, Chicalese BM, An YH, Huynh BH, Bollinger JM Jr (2007) Addition of oxygen to the diiron (II/II) cluster is the slowest step in formation of the tyrosyl radical in the W103Y variant of ribonucleotide reductase protein R2 from mouse. Biochemistry 46:13067CrossRefGoogle Scholar
- 17.Nordlund P, Sjöberg BM, Eklund H (1990) Three-dimensional structure of the free radical protein of ribonucleotide reductase. Nature 345:593Google Scholar
- 21.Ren S, Wang R, Komatsu K, Bonaz-Krause P, Zyrianov Y, McKenna CE, Csipke C, Tokes ZA, Lien EJ (2002) Synthesis, biological evaluation, and quantitative structure-activity relationship analysis of new Schiff bases of hydroxysemicarbazide as potential antitumor agents. J Med Chem 45:410CrossRefGoogle Scholar
- 23.Elford HL (1994) assignee. Method of treating hemoglobinopathies. US Patent 5,366,996Google Scholar
- 24.Basu A, Sinha BN, Saiko P, Graser G, Szekeres T (2011) N-hydroxy-N′-aminoguanidines as anti-cancer lead molecule: QSAR, synthesis and biological evaluation. Bioorg Med Chem Lett 21:3324Google Scholar
- 25.Saiko P, Graser G, Giessrigl B, Lackner A, Grusch M, Krupitza G, Basu A, Sinha B, Jayaprakash V, Jaeger W (2011) A novel N-hydroxy-N′-aminoguanidine derivative inhibits ribonucleotide reductase activity: effects in human HL-60 promyelocytic leukemia cells and synergism with arabinofuranosylcytosine (Ara-C). Biochem Pharmacol 81:50CrossRefGoogle Scholar
- 29.Lynch J, Juarez-Garcia C, Münck E, Que L Jr (1989) Mössbauer and EPR studies of the binuclear iron center in ribonucleotide reductase from Escherichia coli. a new iron-to-protein stoichiometry. J Biol Chem 264:8091Google Scholar