Inna Rozman GrinbergResearcher

Ribonucleotide reductases (RNRs) provide the building blocks for DNA synthesis and repair. RNRs are essential enzymes in living cells and are important targets in biomedical research. Since adequate amount of functional RNRs is critical for cell survival, their activity and expression are tightly regulated. My research interests focus on transcriptional and allosteric regulation of RNRs.

NrdR - global repressor of RNR genes and potential target in drug developement

Bacteria often possess multiple RNR genes in their genomes.  A small regulatory protein NrdR, discovered in 2006 by myself and coworkers, is a transcription factor repressing RNR gene expression. It affects bacterial fitness, viability and infectivity. NrdR is an interesting target in the development of antimicrobial agents, because it is absent in eukaryotes, but present in the majority of bacteria. 

I aim to reveal:

i) what are the molecular mechanisms by which NrdR controls the transcription of RNR genes

ii) how does the NrdR mode of action vary among different bacteria

iii) can NrdR be targeted in vivo to impair bacterial growth and survival.

I am a part of Britt-Marie Sjöberg research group. We use state-of-the-art biochemical and biophysical technologies as well as bioinformatics and closely collaborate with structural biologists.

I have been awarded a grant from Carl Trygger's foundation for hosting a post-doctoral fellow, whose research focuses on NrdR.

NrdR

Rozman Grinberg I, Martínez-Carranza M, Bimai O, Nouaïria G, Shahid S, Lundin D, Logan DT, Sjöberg BM, Stenmark P. A nucleotide-sensing oligomerization mechanism that controls NrdR-dependent transcription of ribonucleotide reductases. Nat Commun. 2022 May 16;13(1):2700. doi: 10.1038/s41467-022-30328-1. PMID: 35577776; PMCID: PMC9110341.

Grinberg, I., Shteinberg T., Gorovitz B., Aharonowitz Y., Cohen G., Borovok I. (2006). The Streptomyces NrdR transcriptional regulator is a Zn ribbon/ATP cone protein that binds to the promoter regions of class Ia and class II ribonucleotide reductase operons. Journal of Bacteriology 188: 7635-7644.

Torrents E.§, Grinberg I.§, Gorovitz-Harris B., Borovok I., Aharonowitz Y.,  Sjoberg B.M., Cohen G. (2007).  NrdR controls differential expression of the Escherichia coli ribonucleotide reductase genes. Journal of Bacteriology 189:  5012-5021. (§ shared first authorship)

Grinberg, I., Shteinberg T., Hassan Q., Aharonowitz Y., Borovok I., Cohen G. (2009). Functional analysis of the Streptomyces coelicolor NrdR ATP-cone domain: Role in nucleotide binding, oligomerization and DNA interactions. Journal of Bacteriology 191: 1169-1179.

Ribonucleotide reducatases

Bimaï O, Banerjee I, Rozman Grinberg I, Huang P, Lundin D, Sjöberg BM & Logan DT (2023) Activity modulation in anaerobic ribonucleotide reductases: nucleotide binding to the ATP-cone mediates long-range order-disorder transitions in the active site. eLife. doi: 10.7554/eLife.89292.1

Rehling D, Scaletti ER, Rozman Grinberg I, Lundin D, Sahlin M, Hofer A, Sjöberg BM, Stenmark P. Structural and Biochemical Investigation of Class I Ribonucleotide Reductase from the Hyperthermophile Aquifex aeolicus. Biochemistry. 2022 Jan 18;61(2):92-106. doi: 10.1021/acs.biochem.1c00503. Epub 2021 Dec 23. PMID: 34941255; PMCID: PMC8772380.

Hasan M, Banerjee I, Rozman Grinberg I, Sjöberg BM, Logan DT. Solution Structure of the dATP-Inactivated Class I Ribonucleotide Reductase From Leeuwenhoekiella blandensis by SAXS and Cryo-Electron Microscopy. Front Mol Biosci. 2021 Jul 26;8:713608. doi: 10.3389/fmolb.2021.713608. PMID: 34381817; PMCID: PMC8350387.

Rozman Grinberg I, Berglund S, Hasan M, Lundin D, Ho FM, Magnuson A, Logan DT, Sjöberg BM, Berggren G. (2019) Class Id ribonucleotide reductase utilizes a Mn2(IV,III) cofactor and undergoes large conformational changes on metal loading.  Journal of Biological Inorganic Chemistry. 24: 863-877.

Rozman Grinberg I., Lundin D., Sahlin M., Crona M., Berggren G., Hofer A., Sjöberg BM (2018). A glutaredoxin domain fused to the radical-generating subunit of ribonucleotide reductase (RNR) functions as an efficient RNR reductant. Journal of Biological Chemistry 293:15889-15900.

Rozman Grinberg I., Lundin D., Hasan M., Crona M., Jonna VR., Loderer C., Sahlin M., Markova N., Borovok I., Berggren G., Hofer A., Logan DT., Sjöberg BM. (2018) Unique ATP-cone-driven allosteric regulation of ribonucleotide reductase via the radical-generating subunit. eLife 7: e31529.

Loderer C, Jonna VR, Crona M, Rozman Grinberg I, Sahlin M, Hofer A, Lundin D, Sjöberg BM. (2017) A unique cysteine-rich Zn-finger domain present in a majority of class II ribonucleotide reductases mediates catalytic turnover. Journal of Biological Chemistry 292: 19044-19054. Publication selected as one of the Editors’s Pick, i.e. recommended read of the month, by the editors of JBC.

Other publications

Hershko Rimon A, Livnah O, Rozman Grinberg I, Ortiz de Ora L, Yaniv O, Lamed R, Bayer EA, Frolow F, Voronov-Goldman M. Novel clostridial cell-surface hemicellulose-binding CBM3 proteins. Acta Crystallogr F Struct Biol Commun. 2021 Apr 1;77(Pt 4):95-104. doi: 10.1107/S2053230X21002764. Epub 2021 Mar 31. PMID: 33830074; PMCID: PMC8034430.

Rozman Grinberg I, Yaniv O, Ortiz de Ora L, Muñoz-Gutiérrez I, Hershko A, Livnah O, Bayer EA, Borovok I, Frolow F, Lamed R, Voronov-Goldman M. (2019) Distinctive ligand-binding specificities of tandem PA14 biomass-sensory elements from Clostridium thermocellum and Clostridium clariflavum. Proteins 87. doi: 10.1002/prot.25753.

Muñoz-Gutiérrez I, Ortiz de Ora L, Rozman Grinberg I, Garty Y, Bayer EA, Shoham Y, Lamed R, Borovok I. (2016) Decoding Biomass-Sensing Regulons of Clostridium thermocellum Alternative Sigma-I Factors in a Heterologous Bacillus subtilis Host System. PLoS One 11: e0146316.

Dassa B, Utturkar S, Hurt RA, Klingeman DM, Keller M, Xu J, Reddy YH, Borovok I, Rozman Grinberg I, Lamed R, Zhivin O, Bayer EA, Brown SD. (2015) Near-Complete Genome Sequence of the Cellulolytic Bacterium Bacteroides (Pseudobacteroides) cellulosolvens ATCC 35603. Genome Announcements 3: e01022-15.

Petkun S, Rozman Grinberg I, Lamed R, Jindou S, Burstein T, Yaniv O, Shoham Y, Shimon LJ, Bayer EA, Frolow F. (2015) Reassembly and co-crystallization of a family 9 processive endoglucanase from its component parts: structural and functional significance of the intermodular linker. PeerJ 3: e1126.

Rozman Grinberg I, Yin G, Borovok I, Miller ME, Yeoman CJ, Dassa B, Yu Z, Mizrahi I, Flint HJ, Bayer EA, White BA, Lamed R. (2015) Functional phylotyping approach for assessing intraspecific diversity of Ruminococcus albus within the rumen microbiome. FEMS Microbiology Letters 362:1-10.

Levy-Assaraf M, Voronov-Goldman M, Rozman Grinberg I, Weiserman G, Shimon LJ, Jindou S, Borovok I, White BA, Bayer EA, Lamed R, Frolow F. (2013) Crystal structure of an uncommon cellulosome-related protein module from Ruminococcus flavefaciens that resembles papain-like cysteine peptidases. PLoS One 8: e56138.

Moraïs S, Shterzer N, Rozman Grinberg I., Mathiesen G, Eijsink VG, Axelsson L, Lamed R, Bayer EA, Mizrahi I. (2013) Establishment of a simple Lactobacillus plantarum cell consortium for cellulase-xylanase synergistic interactions. Applied and Environmental Microbiology. 79: 5242-5249.

Ben-Dov N, Rozman Grinberg I, Korenstein R. (2012) Electroendocytosis is driven by the binding of electrochemically produced protons to the cell's surface. PLoS One 7: e50299.