PD Dr. Roman Fedorov participates in RESIST research projects D4.
| My Research Interest in RESIST |
The innate immune sensors activate interferon-driven antiviral responses upon recognition of pathogen-associated molecular patterns and serve as a rheostat for the metabolic activity of the microbiota and its exposure to diet, xenobiotics, and infections. The ability to modulate innate immune sensors opens new ways to novel antiviral and anti-inflammatory drugs and therapies against cancer and many aging-associated metabolic, neoplastic, autoimmune, or autoinflammatory disorders. Using unbiased experimental screening combined with computer-aided rational drug design approaches, we aim at developing small-molecule allosteric effectors that specifically enhance or reduce the enzymatic activity of members of the family of innate immune sensors, such as cyclic GMP-AMP synthases (cGAS) and 2′-5′ oligoadenylate synthetases (OAS). To study structural states and conformational changes associated with substrate binding and product release mechanisms of innate immune sensors cGAS and OAS, we apply a combination of three advanced cutting-edge methodologies: time-resolved serial femtosecond crystallography, on-chip substrate or product binding studies, and high-pressure crystallography. The obtained mechanistic information will be used to develop specific allosteric activity modulators of innate immune sensors.
PD Dr. Fedorov about his scientific work
PD Dr. Roman Fedorov – Curriculum Vitae
Current Position
Undergraduate and Postgraduate Training
Academic and Research Posts
Other Scientific Roles
Awards and Prizes
10 Selected Publications
Prakash O, Führing J, Post J, Shepherd SM, Eadsforth TC, Gray D, Fedorov R and Routier FH. Identification of Leishmania major UDP-Sugar Pyrophosphorylase Inhibitors Using Biosensor-Based Small Molecule Fragment Library Screening. (2019) Molecules, 24(5): 996. DOI:10.3390/molecules24050996
Cramer JT, Führing JI, Baruch P, Brütting C, Knölker H-J, Gerardy-Schahn R, and Fedorov R. Decoding Allosteric Networks in Biocatalysts: Rational Approach to Therapies and Biotechnologies. (2018) ACS Catalysis. 8:2683-2692. DOI: 10.1021/acscatal.7b03714
Hirschmann F, Krause F, Baruch P, Chizhov I, Mueller JW, Manstein DJ, Papenbrock J, Fedorov R. Structural and biochemical studies of sulphotransferase 18 from Arabidopsis thaliana explain its substrate specificity and reaction mechanism. (2017) Sci. Rep. 7(1):4160.
Lohöfener J, Steinke N, Kay-Fedorov P, Baruch P, Nikulin A, Tishchenko S, Manstein DJ, and Fedorov R. The activation mechanism of 2’-5’-oligoadenylate synthetase gives new insights into OAS/cGAS triggers of innate immunity. (2015) Structure. 23(5):851-862. DOI: 10.1016/j.str.2015.03.012.
Führing JI, Cramer JT, Schneider J, Baruch P, Gerardy-Schahn R, and Fedorov R. A Quaternary Mechanism Enables the Complex Biological Functions of Octameric Human UDP-glucose Pyrophosphorylase, a Key Enzyme in Cell Metabolism. (2015) Sci. Rep. 5, 9618; DOI:10.1038/srep09618.
Führing J, Cramer JT, Routier FH, Lamerz A-C, Baruch P, Gerardy-Schahn R and Fedorov R. Catalytic mechanism and allosteric regulation of UDP-glucose pyrophosphorylase from Leishmania major. (2013) ACS Catalysis. 3:2976-2985.
Hellert J, Weidner-Glunde M, Krausze J, Richter U, Adler H, Fedorov R, Pietrek M, Rückert J, Ritter C, Schulz TF, Lührs T. A Structural Basis for BRD2/4-Mediated Host Chromatin Interaction and Oligomer Assembly of Kaposi Sarcoma-Associated Herpesvirus and Murine Gammaherpesvirus LANA Proteins. (2013) PLoS Pathog 9(10): e1003640. doi:10.1371/journal.ppat.1003640
Fedorov R, Böhl M, Tsiavaliaris G, Hartmann FK, Taft MH, Baruch P, Brenner B, Martin R, Knölker H-J, Gutzeit HO & Manstein DJ. The mechanism of pentabromopseudilin inhibition of myosin motor activity. (2009) Nature Structural & Molecular Biology, 16, 80-88.
Fedorov R, Witte G, Urbanke C, Manstein DJ, Curth U. 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.
Fedorov R, Vasan R, Ghosh DK and Ilme Schlichting. Structures of nitric oxide synthase isoforms complexed with the inhibitor AR-R17477 suggest a rational basis for specificity and inhibitor design. (2004) PNAS 101, 5892-5897.
