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Macromolecular Mechanisms

PD Dr. Roman Fedorov

Phone: +49 511 532 3705
Fax:      +49 511 532 5966




Research Focus

Our research is focused on fundamental studies of the molecular mechanisms underlying the function of nucleotidyltransferases and the development of new medical applications involving these enzymes. The nucleotidyltransferases form a large superfamily of proteins involved in many key cellular processes, including RNA polyadenylation and editing, DNA repair, chromatin remodelling, regulation of protein activity, intracellular signal transduction and antibiotic resistance. They catalyze the nucleoside monophosphate transfer from NTP to an acceptor group belonging to a protein, nucleic acid or small molecule. Allosteric regulation plays an important functional role on all levels of structural organisation of these proteins. The nucleotidyltransferase function can be affected by single amino-acid residues located far away from the active site, by functional loops and other elements of secondary structure, by substrate induced changes in tertiary structure and by the different oligomerization states. Elucidating these complex mechanisms and structure-function relationships in nucleotidyltransferases is essential for understanding fundamental biological processes regulated by these enzymes, and for drug-design and biotechnological applications.


Allosteric regulation of UDP-glucose and UDP-sugar pyrophosphorylases: a way to design new anti-leishmanial drugs

Parasites of the Trypanosomatidae family include Trypanosoma brucei, Trypanosoma cruzi and several Leishmania species that cause major diseases in humans. The diseases caused by these pathogens cause about 60 million deaths annually. To date there are no vaccines or effective drugs to fight these parasites. Several reports highlight the importance of the central nucleotide sugar UDP-glucose (UDP-Glc) in the growth of trypanosomatid parasites. It was demonstrated that suppressing the biosynthesis of UDP-galactose (UDP-Gal) leads to cessation of the parasites’ growth. The enzymes involved in UDP-Gal/UDP-Glc biosynthesis are thus potential drug targets in these organisms.
This project is focused on the development of highly-specific allosteric inhibitors of L. major UGP and USP that will be used as drug candidates. The project combines two lines of research. One line involves mechanistic studies to provide a description of the complete L. major UGP and USP enzymatic cycles. In another line of the project we utilize the mechanistic information to construct and optimize specific allosteric inhibitors.

The project is conducted by Johannes Cramer, Petra Baruch and Dr. Roman Fedorov in close cooperation with Prof. Dr. Rita Gerardy-Schahn, Dr. Jana Führing and Prof. Dr. Françoise Routier from the Institute for Cellular Chemistry, Hannover Medical School.  

Designing allosteric OAS activators as potential anti-viral agents

An early response to acute viral infection is the production of interferon by the infected cell. Interferons induce an antiviral state resulting from enhanced transcription of many genes, including 2’-5’-oligoadenylate synthases (OASes). The OASes are nonprocessive nucleotidyltransferases which in vitro utilize a broad range of substrates. OASes are activated by binding to dsRNA, a PAMP produced during viral replication. OASes then convert ATPs to 2’-5’-linked oligoadenylates (2-5A). 2-5A binds to a latent RNase L and triggers the formation of the active dimeric enzyme, which degrades viral and some cellular RNAs, blocking viral spread. Many viruses possess mechanisms to evade this pathway: for example, herpesviruses and the influenza A viruses camouflage the dsRNA with a protein coat. The OASes therefore remain latent. Activation of OAS with exogenous compounds would overcome this mechanism of viral evasion and lead to degradation of viral RNA.

This project is focused on the study of molecular mechanisms of OAS activation, substrate binding, catalysis and product release and development of small-molecule allosteric activators of OAS.

The project is conducted by Jan Lohöfener, Petra Baruch and Dr. Roman Fedorov in close cooperation with Dr. Penelope Kay-Fedorov (Institute for Virology) and Prof. Dr. Dietmar J. Manstein (Institute for Biophysical Chemistry) from Hannover Medical School, and with Dr. Alexey Nikulin, Dr. Svetlana Tishchenko, Prof. Dr. Maria Garber and Prof. Dr. Stanislav Nikonov from the Institute of Protein Research, Russian Academy of Science.  


Petra Baruch
Phone: +49 511 532 4420
Fax:     +49 511 532 5966



In our work we use a highly interdisciplinary approach combining wide range of methods from the fields of biochemistry, biophysics, structural and molecular biology, physical and quantum chemistry, molecular modelling and drug-design. Particularly in X-ray crystallography applications we use various implementations of MR, MIR, MAD, SAD and their combinations; methods of Kinetic Crystallography and Cryo-Crystallography. For structural studies and other experiments involving biophysical methods we use the facilities of the Institute for Biophysical Chemistry / Structure Analysis (Prof. Dr. Dietmar J. Manstein) as well as synchrotron radiation sources: ESRF (Grenoble, France), DESY (Hamburg, Germany), BESSY (Berlin, Germany) and MAX II (Lund, Sweden). For protein production, enzymatic kinetics experiments and functional tests of the inhibitors and effectors we use the facilities of the Institute for Cellular Chemistry (Prof. Dr. Rita Gerardy-Schahn) and the Institute for Virology (Prof. Dr. Thomas Schulz). The small molecule inhibitors and effectors are synthesized in cooperation with Prof. Dr. Chris Meier (University of Hamburg).

Our Cooperation Partners

Our ongoing projects are conducted together with:

Institute for Biophysical Chemistry, Hannover Medical School
Prof. Dr. Dietmar J. Manstein, Dr. Ute Curth, Dr. Igor Chizhov, Dr. Elena Korenbaum

Institute for Cellular Chemistry, Hannover Medical School
Prof. Dr. Rita Gerardy-Schahn, Dr. Jana Führing and Prof. Dr. Francoise Routier

Institute for Virology, Hannover Medical School
Dr. Penelope Kay-Fedorov

Institute of Protein Research, Russian Academy of Science
Dr. Alexey Nikulin, Dr. Svetlana Tishchenko, Prof. Dr. Maria Garber and Prof. Dr. Stanislav Nikonov

Department of Chemistry, Organic Chemistry, University of Hamburg
Prof. Dr. Chris Meier

Our Sponsors

Intramural grant ("HiLF") of Hannover Medical School

Hannover Biomedical Research School (HBRS) and the PhD program Molecular Medicine

About the Group

Our group was founded in 2012 with the support from Prof. Dr. Dietmar J. Manstein (Institute for Biophysical Chemistry) and Prof. Dr. Rita Gerardy-Schahn (Institute for Cellular Chemistry), Hannover Medical School.


Dietmar J. Manstein, Roman Fedorov, Georgios Tsiavaliaris, Hans-Joachim Knölker, René Martin, Juliane Kirst, Herwig O. Gutzeit, Markus Böhl, Marcus Furch. „Means for treating myosin-related diseases“ (WO/2009/065600), International Application No.: PCT/EP2008/009891; Publication Date: 28.05.2008; International Filing Date: 21.11. 2008.


  1. Heissler SM, Selvadurai J, Bond LM, Fedorov R, Kendrick-Jones J, Buss F, Manstein DJ. Kinetic properties and small-molecular inhibition of human myosin-6. (2012) FEBS Lett. 586(19):3208-14.

  2. Preller M, Bauer S, Adamek N, Fujita-Becker S, Fedorov R, Geeves MA, Manstein DJ. Structural basis for the allosteric interference of myosin function by reactive thiol region mutations G680A and G680V. (2011) J. Biol. Chem. 286(40), 35051-35060.

  3. Chinthalapudi K, Taft MH, Martin R, Heissler SM, Preller M, Hartmann FK, Brandstaetter H, Kendrick-Jones J, Tsiavaliaris G, Gutzeit HO, Fedorov R, Buss F, Knölker HJ, Coluccio LM, Manstein DJ. Mechanism and Specificity of Pentachloropseudilin-mediated Inhibition of Myosin Motor Activity. (2011) J. Biol. Chem. 286(34), 29700-8.

  4. Naue N, Fedorov R, Pich A, Manstein DJ, Curth U. Site-directed mutagenesis of the χ subunit of DNA polymerase III and single-stranded DNA-binding protein of E. coli reveals key residues for their interaction. (2011) Nucleic Acids Res. 39(4), 1398-407.

  5. Mamta Amrute-Nayak, Ralph P. Diensthuber, Walter Steffen, Daniela Kathmann, Falk K. Hartmann, Roman Fedorov, Claus Urbanke, Dietmar J. Manstein, Bernhard Brenner, and Georgios Tsiavaliaris. Targeted optimization of a protein nanomachine for operation in biohybrid devices. (2010) Angew. Chem. Int. Ed. 49, 312-316.

  6. René Martin, Anne Jäger, Markus Böhl, Sabine Richter, Roman Fedorov, Dietmar J. Manstein, Herwig O. Gutzeit, and Hans-Joachim Knölker. Total Synthesis of Pentabromo- and Pentachloropseudilin, and Synthetic Analogues—Allosteric Inhibitors of Myosin ATPase. (2009) Angew. Chem. Int. Ed. 48, 8042 –8046.

  7. René Martin, Anne Jäger, Markus Böhl, Sabine Richter, Roman Fedorov, Dietmar J. Manstein, Herwig O. Gutzeit, and Hans-Joachim Knölker. Total Synthesis of Pentabromo- and Pentachloropseudilin, and Synthetic Analogues—Allosteric Inhibitors of Myosin ATPase. (2009) Angew. Chem. 121, 8186 –8190.

  8. Roman Fedorov, Markus Böhl, Georgios Tsiavaliaris, Falk K. Hartmann, Manuel H. Taft, Petra Baruch, Bernhard Brenner, Rene Martin, Hans-Joachim Knölker, Herwig O. Gutzeit & Dietmar J. Manstein. The mechanism of pentabromopseudilin inhibition of myosin motor activity. (2009) Nature Structural & Molecular Biology, 16, 80-88.

  9. Elena Stolboushkina, Stanislav Nikonov, Alexei Nikulin, Udo Bläsi, Dietmar J. Manstein, Roman Fedorov, Maria Garber and Oleg Nikonov. Crystal Structure of the Intact Archaeal Translation Initiation Factor 2 Demonstrates Very High Conformational Flexibility in the α- and β- Subunits. (2008) J. Mol. Biol. 382, 680-691.

  10. Gregor Witte, Roman Fedorov and Ute Curth. Biophysical analysis of Thermus aquaticus single-stranded DNA binding protein. (2008) Biophys. J., 94(6), 2269-2279.

  11. Oleg Nikonov, Elena Stolboushkina, Alexei Nikulin, David Hasenöhrl, Udo Bläsi, Dietmar J. Manstein, Roman Fedorov, Maria Garber and Stanislav Nikonov. New insights into the interactions of the translation initiation factor 2 from archaea with guanine nucleotides and initiator tRNA. (2007) J. Mol. Biol. 373(2), 328-336.

  12. Roman Fedorov, Gregor Witte, Claus Urbanke, Dietmar J. Manstein, Ute Curth. 3D structure of Thermus aquaticus single-stranded DNA-binding protein gives insight into the functioning of SSB proteins. (2006). Nucleic Acids Res 34, 6708-6717.

  13. Tatiana Domratcheva, Roman Fedorov, Ilme Schlichting. Analysis of the Primary Photocycle Reactions Occurring in the Light, Oxygen, and Voltage Blue-Light Receptor by Multiconfigurational Quantum-Chemical Methods. (2006) J. Chem. Theory Comput.; 2(6), 1565 – 1574.

  14. Hans Matter, H. S. Arun Kumar, Roman Fedorov, Armin Frey, Peter Kotsonis, Elisabeth Hartmann, Lothar G. Fröhlich, Andreas Reif, Wolfgang Pfleiderer, Peter Scheurer, Dipak K. Ghosh, Ilme Schlichting, and Harald H. H. W. Schmidt. Structural Analysis of Isoform-Specific Inhibitors Targeting the Tetrahydrobiopterin Binding Site of Human Nitric Oxide Synthases. (2005) J. Med. Chem., 48(15), 4783-4792.

  15. Michael A. Geeves, Roman Fedorov, and Dietmar J. Manstein. Actomyosin: mechanism of chemo-mechanical coupling. (2005) CMLS, Cell. Mol. Life Sci. 62, 1462-1477.

  16. Roman Fedorov, Ryan Vasan, Dipak K. Ghosh, and Ilme Schlichting. Structures of nitric oxide synthase isoforms complexed with the inhibitor AR-R17477 suggest a rational basis for specificity and inhibitor design. PNAS (2004) 101, 5892-5897.

  17. Tilman Kottke, Bernhard Dick, Roman Fedorov, Ilme Schlichting, Rainer Deutzmannm, Peter Hegemann. Irreversible Photoreduction of Flavin in a Mutated Phot-LOV1 Domain. Biochemistry (2003) 42, 9854-9862.

  18. Roman Fedorov, Elisabeth Hartmann, Dipak K. Ghosh, and Ilme Schlichting. Structural basis for the specificity of the nitric oxide synthase inhibitors W1400 and Nω-propyl-L-Arg for the inducible and neuronal isoforms. J. Biol. Chem., (2003) 278, 45818-45825.

  19. Roman Fedorov, Ilme Schlichting, Elisabeth Hartmann, Tatjana Domratcheva, Markus Fuhrmann and Peter Hegemann. Crystal structures and molecular mechanism of a light induced signaling switch: the Phot-LOV1 domain from Chlamydomonas reinhardtii. Biophysical J. (2003) 84, 2474-2482.

  20. Roman Fedorov, Dipak K. Ghosh, and Ilme Schlichting. Crystal structures of cyanide complexes of P450cam and the oxygenase domain of inducible nitric oxide synthase – structural models of the short-lived oxygen complexes. Archives of Biochemistry and Biophysics. (2003) 409, 25-31.

  21. Natalia Nevskaya, Svetlana Tishchenko, Mikhail Paveliev, Yulia Smolinskaya, Roman Fedorov, Wolfgang Piendl, Yoshikazu Nakamura, Tomohiko Toyoda, Maria Garber and Stanislav Nikonov. Structure of ribosomal protein L1 from Methanococcus thermolithotrophicus. Functionally important structural invariants on the L1 surface. Acta Cryst. (2002) D58, 1023-1029.

  22. Roman Fedorov, Vladimir Meshcheryakov, George Gongadze, Natalia Fomenkova, Natalia Nevskaya, Maria Selmer, Martin Laurberg, Ole Kristensen, Salam Al-Karadaghi, Anders Liljas, Maria Garber and Stanislav Nikonov. Structure of ribosomal protein TL5 complexed with RNA provides new insights into the CTC family of stress proteins. Acta Cryst. (2001) D57, 968-976.

  23. Natalia Davydova, Roman Fedorov, Victor Streltsov, Anders Liljas and Maria Garber. Crystals of a mutant form of ribosomal protein L22 rendering bacterial ribosomes resistant to erythromycin. Acta Cryst. (2001) D57, 1150-1152.

  24. Gongadze G.M., Perederina A.A., Meshcheryakov V.A., Fedorov R.V., Moskalenko S.E., Rak A.V., Serganov A.A., Shcherbakov D.V., Nikonov S.V., and Garber M.B. The Thermus thermophilus 5S rRNA-protein complex: Identification of specific binding sites for proteins L5 and L18 in the 5S rRNA. Molecular Biology (Moscow) (2001) 35, 610-616.

  25. Rak, A., Fedorov, R., Alexandrov, K., Albert, S., Goody, R.S., Gallwitz, D., & Scheidig, A.J. Crystal structure of the GAP domain of Gyp1p: first insights into interaction with Ypt/Rab proteins. The EMBO Journal (2000) 19(19), 5105-5113.

  26. Natalia Nevskaya, Svetlana Tishchenko, Roman Fedorov, Salam Al-Karadaghi, Anders Liljas, Alex Kraft, Wolfgang Piendl, Maria Garber and Stanislav Nikonov. Archaeal ribosomal protein L1: the structure provides new insights into RNA binding of the L1 protein family. Structure with Folding & Design (2000) 8(4), 363-371.

  27. Roman Fedorov, Natalia Nevskaya, Alphia Khairullina, Svetlana Tishchenko, Albert Mikhailov, Maria Garber and Stanislav Nikonov. Structure of ribosomal protein L30 from Thermus thermophilus at 1.9A resolution: conformational flexibility of the molecule. Acta Cryst. (1999) D55, 1827-1833.

  28. S.V.Nikonov, N.A.Nevskaya, N.P.Fomenkova, A.D.Nikulin, R.V.Fedorov, I.A.Eliseikina, S.V.Tishchenko, M.B.Garber. Structural Investigations of Bacterial Ribosomal Proteins. Surface. X-Ray, Synchrotron and Neutron Studies (1999) 2, 6-9.

  29. Chen Z., Baruch P., Mathews F.S., Matsushita K., Yamashita T., Toyama H., Adachi O. Crystallization and preliminary diffraction studies of two quinoprotein alcohol dehydrogenases (ADHs): a soluble monomeric ADH from Pseudomonas putida HK5 (ADH-IIB) and a heterotrimeric membrane-bound ADH from Gluconobacter suboxydans (ADH-GS). (1999) Acta Cryst. D55, 1933-1936.

  30. S.V.Nikonov, N.A.Nevskaya, R.V.Fedorov, A.R.Khairullina, S.V.Tishchenko, A.D.Nikulin and M. B. Garber. Structural Studies of Ribosomal Proteins. Biol. Chem. (1998) 379, 795-805.

  31. M.Garber, N.Davydova, R.Fedorov, G.Gongadze, A.Kalinin, V.Meshcheryakov, S.Moskalenko, E.Mudrik, N.Nevskaya, S.Nikonov, A.Nikulin, A.Peredelina, A.Rak, A.Serganov, D.Shcherbakov, O.Tin, S.Tishchenko, J.Vassilieva, A.Kraft, W.Piendl, C.Ehresmann, B.Ehresmann, P.Allard, M.Helgstrand, T.Hard. Ribosomal proteins: Crystallization, crystallographic and solution studies. The Proceedings of the workshop on "Structure Research of the Ribosome and its functional complexes", GKSS Research Center Greesthacht GmbH, Greesthacht, Germany,  9-11.09.1998, pp.47-51.

  32. S.V.Nikonov, N.P.Fomenkova, A.D.Nikulin, R.V.Fedorov, N.A.Nevskaya. The ribosome structure: RNA-protein and protein-protein interactions. Molecular Biology (Moscow) (1998) 32 (5), 773-781.

  33. R.V. Fedorov. Quasi-Degenerate Perturbation Theory for Intermediate Hamiltonians in application to the calculations of low-lying electronic states of Fe, Ni and Ti. Vestnik MGU, series 2, Chemistry (1997) 38 (1), 17-20.