natalliastrushkevich

Natallia Strushkevich

Assistant Professor
Center for Molecular and Cellular Biology

Dr. Strushkevich received her PhD in Biochemistry from the Institute of Bioorganic Chemistry (Belarus). She carried out postdoctoral research at Osaka University and the University of Toronto. Successfully set up the Human Cytochrome P450 (CYP) project as part of the Structural Biology platform at the Structural Genomics Consortium (Canada). Applied an extensive protein family approach for structure-function studies of 57 human CYP enzymes using molecular biology, enzymology and X-ray crystallography. This effort lead to the resolution and deposition in the PDB of more than a dozen CYP structures in complex with vitamin D3 and derivatives, cholesterol and derivatives, steroids and various drugs, and inhibitors related to antifungal infections, hypertension and metabolic disorders. She is an internationally recognized expert in cytochrome P450 field and a co-founder of two biotech start-ups, involved in discovery and development of novel therapeutics.

Cytochrome P450 (CYP) is a superfamily of hemeproteins found in all kingdoms of life. In humans, they metabolize both endogenous compounds and drugs. CYP-mediated drug metabolism is an obligatory checkpoint for all drug candidates before the FDA approval as prescription drugs. On the other hand, some CYPs are drug targets themselves as they catalyze crucial reactions in cholesterol, vitamin D3, eicosanoids and steroid hormones synthesis affecting human health and sexual development. With the focus on latter group, we developed a technological platform CRYSTA, which combines a number of techniques and know-hows oriented for rational drug design to selected CYP targets.
My research within CDISE will focus on combining of experimental data with computational approaches and machine learning for design and development of: a) protein-protein interaction (PPI) inhibitors (applicable in breast and prostate cancers) and activators (Alzheimer disease) b) novel scaffolds for inhibition of evaluated target enzymes (infectious diseases) c) prediction of drug metabolism by cytochrome P450 enzymes. The combination of experimental data and powerful computational algorithms aims to accelerate drug discovery using largely unexplored chemical space.

  1. Masamrekh R.A., Kuzikov A.V., Haurychenka Y.I., Shcherbakov K.A., Veselovsky A.V., Filimonov D.A., Dmitriev A.V., Zavialova M.G., Gilep A.A., Shkel T.V., Strushkevich N.V., Usanov S.A., Archakov A.I., Shumyantseva V.V. In vitro interactions of abiraterone, erythromycin, and CYP3A4: implications for drug-drug interactions. Fundam Clin Pharmacol. 2019 Jul 8. doi: 10.1111/fcp.12497. PubMed PMID: 31286572.
  2. Grabovec I.P., Smolskaya S.V., Baranovsky A.V., Zhabinskii V.N., Dichenko Y.V., Shabunya P.S., Usanov S.A., Strushkevich N.V. Ligand-binding properties and catalytic activity of the purified human 24-hydroxycholesterol 7α-hydroxylase, CYP39A1. J Steroid Biochem Mol Biol. 2019; 193:105416. doi: 10.1016/j.jsbmb.2019.105416. PubMed PMID: 31247323.
  3. Yablokov E.O., Sushko T.A., Ershov P.V., Florinskaya A.V., Gnedenko O.V., Shkel T.V., Grabovec I.P., Strushkevich N.V., Kaluzhskiy L.A., Usanov S.A., Gilep A.A., Ivanov A.S. A large-scale comparative analysis of affinity, thermodynamics and functional characteristics of interactions of twelve cytochrome P450 isoforms and their redox partners. 2019; 162:156-166. doi:10.1016/j.biochi.2019.04.020. PubMed PMID: 31034920.
  4. Gnedenko O.V., Yablokov E.O., Ershov P.V., Svirid A.V., Shkel T.V., Haidukevich I.V., Strushkevich N.V., Gilep A.A., Usanov S.A., Ivanov A.S. Interaction of prostacyclin synthase with cytochromes P450. Biomed Khim. 2019; 65(1):63-66.
  5. Kuzikov A., Masamrekh R., Shkel T., Strushkevich N., Gilep A., Usanov S., Archakov A., Shumyantseva V. Assessment of electrocatalytic hydroxylase activity of cytochrome P450 3A4 (CYP3A4) by means of derivatization of 6β-hydroxycortisol by sulfuric acid for fluorimetric assay. Talanta. 2019; 196:231-236.
  6. Usanov S.A., Kliuchenovich A.V., Strushkevich N.V. Drug design strategies for Cushing’s syndrome. Expert Opin Drug Discov. 2018 20:1-9. doi: 10.1080/17460441.2019.1559146.
  7. Dalidovich T.S., Hurski A.L., Morozevich G.E., Latysheva A.S., Sushko T.A., Strushkevich N.V., Gilep A.A., Misharin A.Y., Zhabinskii V.N., Khripach V.A. New azole derivatives of [17(20)E]-21-norpregnene: Synthesis and inhibition of prostate carcinoma cell growth. Steroids. 2018; S0039-128X(18)30156-9.
  8. Masamrekh R., Kuzikov A., Veselovsky A., Toropygin I., Shkel T., Strushkevich N., Gilep A., Usanov S., Archakov A., Shumyantseva V. Interaction of 17α-hydroxylase, 17(20)-lyase (CYP17A1) inhibitors – abiraterone and galeterone – with human sterol 14α-demethylase (CYP51A1). J Inorg Biochem. 2018; 186:24-33.
  9. Svirid A.V., Ershov P.V., Yablokov E.O., Kaluzhskiy L.A., Mezentsev Y.V., Florinskaya A.V., Sushko T.A., Strushkevich N.V., Gilep A.A., Usanov S.A., Medvedev A.E., Ivanov A.S. Direct Molecular Fishing of New Protein Partners for Human Thromboxane Synthase. Acta Naturae. 2017; 9(4):92-100.
  10. Yablokov E., Florinskaya A., Medvedev A., Sergeev G., Strushkevich N., Luschik A., Shkel T., Haidukevich I., Gilep A., Usanov S., Ivanov A. Thermodynamics of interactions between mammalian cytochromes P450 and b5. Arch Biochem Biophys. 2017; 619:10-15.
  11. Davydov R., Strushkevich N., Smil D., Yantsevich A., Gilep A., Usanov S., Hoffman B.M. Evidence that Compound I is the active species in both the hydroxylase and lyase steps by which P450scc converts cholesterol to pregnenolone: EPR/ENDOR/Cryoreduction/Annealing studies. Biochemistry. 2015; 54(48):7089-97.
  12. Kaluzhsiy L.A., Gnedenko O.V., Gilep A.A., Strushkevich N.V., Shkel T.V., Chernovetsky M.A., Ivanov A.S., Lisitsa A.V., Usanov A.S., Stonik V.A., Archakov A.I. The screening of the inhibitors of the human cytochrome P450(51) (CYP51A1): the plant and animal structural lanosterol’s analogs. Biomed Khim. 2014; 60(5):528-37.
  13. Tempel W., Grabovec I., MacKenzie F., Dichenko Y.V., Usanov S.A., Gilep A.A., Park H.W., Strushkevich N. Structural characterization of human cholesterol 7α-hydroxylase. Lipid Res. 2014; 55(9):1925-32.
  14. Yantsevich A.V., Dichenko Y.V., Mackenzie F., Mukha D.V., Baranovsky A.V., Gilep A.A., Usanov S.A., Strushkevich N.V. Human steroid and oxysterol 7α-hydroxylase CYP7B1: substrate specificity, azole binding and misfolding of clinically relevant mutants. FEBS J. 2014; 281(6):1700-13.
  15. Strushkevich N., Gilep A.A., Shen L., Arrowsmith C.H., Edwards A.M., Usanov S.A., Park H.W. Structural insights into aldosterone synthase substrate specificity and targeted inhibition. Mol. 2013;27(2):315-24.
  16. Davydov R., Gilep A.A., Strushkevich N.V., Usanov S.A., Hoffman B.M. Compound I is the reactive intermediate in the first monooxygenation step during conversion of cholesterol to pregnenolone by cytochrome P450scc: EPR/ENDOR/Cryoreduction/Annealing Studies. Am. Chem. Soc. 2012, 134(41), 17149-17156.
  17. Strushkevich N., MacKenzie F., Cherkesova T., Grabovec I., Usanov S.A., Park H.W. Structural basis for pregnenolone biosynthesis by the mitochondrial monooxygenase system. Natl. Acad. Sci. USA, 2011, 108(25), 10139-10143.
  18. Strushkevich N.V., Harnastai I.N., Usanov S.A. Mechanism of steroidogenic electron transport: role of conserved Glu429 in destabilization of CYP11A1-adrenodoxin complex. Biochemistry (Mosc). 2010, 75(5), 570-578.
  19. Strushkevich N., Usanov S, Park H-W. Human Vitamin D 25-Hydroxylase: Structure and Function Vitamin D: Nutrition, Side Effects and Supplements, 2010, 207-222 (Editor: S.R. Malone, Nova Science Publishers, Inc., New York). Book Chapter
  20. Strushkevich N., Usanov S.A., Park H.W. Structural basis of human CYP51 inhibition by antifungal azoles. Mol. Biol. 2010, 397(4), 1067-1078.
  21. Strushkevich N., Usanov S.A., Plotnikov A.N., Jones G., Park H.W. Structural analysis of CYP2R1 in complex with vitamin D3. Mol. Biol. 2008, 380(1), 95-106.
  22. Strushkevich N.V., Harnastai I.N., Lepesheva G.I., Usanov S.A. Role of C-terminal sequence of cytochrome P450scc in folding and functional activity. Biochemistry (Mosc). 2006, 71(9), 1027-10
  23. Min L., Strushkevich N.V., Harnastai I.N., Iwamoto H., Gilep A.A., Takemori H., Usanov S.A., Nonaka Y., Hori H., Vinson G.P., Okamoto M. Molecular identification of adrenal inner zone antigen as a heme-binding protein. FEBS J. 2005, 272(22), 5832-58
  24. Strushkevich N.V., Azeva T.N., Lepesheva G.I., Usanov S.A. Role of positively charged residues lys267, lys270, and arg411 of cytochrome p450scc (CYP11A1) in interaction with adrenodoxin. Biochemistry (Mosc). 2005, 70(6), 664-6
  25. Usanov S.A., Graham S.E., Lepesheva G.I., Azeva T.N., Strushkevich N.V., Gilep A.A., Estabrook R.W., Peterson J.A. Probing the interaction of bovine cytochrome P450scc (CYP11A1) with adrenodoxin: evaluating site-directed mutations by molecular modeling. 2002, 41(26), 8310-8320.
  26. Azeva T.N., Gilep A.A., Lepesheva G.I., Strushkevich N.V., Usanov S.A. Site-directed mutagenesis of cytochrome P450scc. II. Effect of replacement of the Arg425 and Arg426 residues on the structural and functional properties of the cytochrome P450scc. Biochemistry (Mosc). 2001, 66(5), 564-5
  27. Lepesheva G.I, Azeva T.N, Strushkevich V., Gilep A.A., Usanov S.A. Site-directed mutagenesis of cytochrome P450scc (CYP11A1). Effect of lysine residue substitution on its structural and functional properties. Biochemistry (Mosc). 2000, 65(12), 1409-1418.
  28. Lepesheva G.I., Strushkevich N.V., Usanov S.A. Conformational dynamics and molecular interaction reactions of recombinant cytochrome p450scc (CYP11A1) detected by fluorescence energy transfer. Biochim Biophys Acta. 1999, 1434(1), 31-43.
  29. Lepesheva G.I., Azeva T.N., Strushkevich N.V., Adamovich T.B., Cherkesova T.S., Usanov S.A. Comparative structural-functional characterization of recombinant and natural adrenodoxin. Interaction with cytochrome P450scc. Biochemistry (Mosc). 1999, 64(9), 1079-10

CRYSTAL STRUCTURES 

PDB ID, Structure Title, Dep. Date, Resolution, PDB DOI
3C6G,”Crystal structure of CYP2R1 in complex with vitamin D3″,”2008-02-04″,”2.80″, “10.2210/pdb3c6g/pdb”
3CZH,”Crystal structure of CYP2R1 in complex with vitamin D2″,”2008-04-29″ ,”2.30″, 10.2210/pdb3czh/pdb”
3DAX,”Crystal structure of human CYP7A1″,”2008-05-30″,”2.15″,”10.2210/pdb3dax/pdb”
3DL9,”Crystal structure of CYP2R1 in complex with 1-alpha-hydroxy-vitamin D2″,”2008-06-26″, “2.72”, “10.2210/pdb3dl9/pdb”
3JUS,”Crystal structure of human lanosterol 14alpha-demethylase (CYP51) in complex with econazole”, “2009-09-15″,”2.90″,”10.2210/pdb3jus/pdb”
3JUV,”Crystal structure of human lanosterol 14alpha-demethylase (CYP51)”,”2009-09-15″, “3.12”, “10.2210/pdb3juv/pdb”
3LD6,”Crystal structure of human lanosterol 14alpha-demethylase (CYP51) in complex with ketoconazole”,”2010-01-12″,”2.80″,”10.2210/pdb3ld6/pdb”
3N9Y,”Crystal structure of human CYP11A1 in complex with cholesterol”,”2010-05-31″, “2.10”, “10.2210/pdb3n9y/pdb”
3N9Z,”Crystal structure of human CYP11A1 in complex with 22-hydroxycholesterol”,”2010-05-31″, “2.17”,”10.2210/pdb3n9z/pdb”
3NA0,”Crystal structure of human CYP11A1 in complex with 20,22-dihydroxycholesterol”,”2010-05-31″, “2.50”,”10.2210/pdb3na0/pdb”
3NA1,”Crystal structure of human CYP11A1 in complex with 20-hydroxycholesterol”,”2010-05-31″, “2.25”,”10.2210/pdb3na1/pdb”
3SN5,”Crystal structure of human CYP7A1 in complex with cholest-4-en-3-one”,”2011-06-28″, “2.75”, “10.2210/pdb3sn5/pdb”
3V8D,”Crystal structure of human CYP7A1 in complex with 7-ketocholesterol”,”2011-12-22″, “1.90”, “10.2210/pdb3v8d/pdb”
4DVQ,”Structure of human aldosterone synthase, CYP11B2, in complex with deoxycorticosterone”, “2012-02-23″,”2.49″,”10.2210/pdb4dvq/pdb”
4FDH,”Structure of human aldosterone synthase, CYP11B2, in complex with fadrozole”,”2012-05-28″, “2.71”,”10.2210/pdb4fdh/pdb”
  • Team award of the Russian Academy of Sciences and the National Academy of Sciences of Belarus of 2018 in natural sciences for the series of works “Protein biochemistry of cytochrome P450-dependent monooxygenase systems”.
  • Top 10 results of the National Academy of Sciences of Belarus of 2015 in the field of fundamental and applied research.
  • Top 10 results of the National Academy of Sciences of Belarus of 2014 in the field of fundamental and applied research.
  • Laureate of the National Academy of Sciences of Belarus Prizes of 2013 in the field of chemical and earth sciences.
  • Louis T.J. Delbaere Award for the best poster at the Canadian Light Source 13th Annual Users’ Meeting, 2010, Saskatoon, Canada
  • Best Poster Award at the 16th International Conference on Cytochrome P450, 2009, Okinawa, Japan
  • Best Research Study Award from the Presidium of the National Academy of Sciences (NAS) of Belarus for the excellence in Biochemistry, 2004, Minsk, Belarus