Galina Lepesheva
Last active: 9/17/2021

Profile

Lepesheva lab research

Our general area of research interest lies at the interface between biochemistry, structural biology and medicine and is focused on the cytochrome P450 family 51 (sterol 14a-demethylases, also known as CYP51). This P450 enzyme is involved in sterol biosynthesis, the ancient metabolic pathway that emerged upon accumulation of molecular oxygen in the Earth's atmosphere and resulted in the development of eukaryotic membranes and a variety of regulatory pathways that control the fate and function of different cell types. There are branches of this pathway that vary across phylogeny, but demethylation of the C-14 atom on the sterol core is conserved from bacteria to mammals. This reaction includes three monooxygenation cycles (two hydroxylations and one C-C bond cleavage), all of them being catalyzed by one enzyme.   

For more than 50 years, the CYP51 reaction has served as the target for clinical antifungal drugs and agricultural fungicides, yet the enzyme per se has not been included in the drug discovery process due to the difficulties of its handling. Our long-term goal is to understand what makes/keeps a CYP51 a CYP51 and what structural features of this P450 can be used to direct design of potent, efficient, and species-selective inhibitors. We have determined crystal structures of CYP51 orthologs from pathogenic protozoa (Trypanosoma cruzi [Chagas disease], Trypanosoma brucei [sleeping sickness], and Leishmania infantum [visceral leishmaniasis]) and fungi (Aspergillus fumigatus and Candida albicans, the two leading invasive fungal killers) as well as from human and from a sterol-making bacterium Methylococcus capsulatus. We studied CYP51 inhibition, screened for new inhibitory chemotypes, identified a new highly potent inhibitory scaffold (VNI), non-toxic and curative in mouse models of Chagas disease, and explored structure-based design for its further pathogen-specific development. A small in-house library of analogs with enhanced antiprotozoal, antifungal, and anticancer activities has been synthesized and is under testing in cellular experiments and in vivo. By solving the structures of CYP51s in complex with their sterol substrates, we found that while upon binding of inhibitory ligands (azoles, pyridines, and even a substrate analog) CYP51s remain in their open (ligand-free like) state, binding of the physiological substrates causes a large-scale conformational switch that is conserved across biological kingdoms and involves rearrangements in the backbone of the active site cavity inside the hemoprotein, closing the substrate entrance on the distal, membrane-immersed surface of the molecule and changing the electrostatic potential on the opposite, proximal surface (the surface of interaction with the electron donor partner). Through the expression of gene mutated constructs we have evidenced that these movements are required to prepare the enzyme for catalysis.

Our ongoing research involves three aims 1) to determine, by combining cryo-electron microscopy and X-ray crystallography, the structures of the complex of the substrate-bound protozoan and human CYP51 with the (eukaryotic) CYP51 electron donor protein cytochrome P450 reductase (CPR) and the structure of the substrate-bound Methylococcus capsulatus CYP51/ferredoxin fusion protein; 2) to apply computational structural biology to better understand CYP51 molecular dynamics; 3) to evaluate the efficacy of our CYP51 inhibitors (VNI derivatives with optimized pharmacokinetics) in the mouse models of drug resistant Chagas disease (Colombiana Trypanosoma cruzi) and in the mouse model of sleeping sickness (Trypanosoma brucei), to analyze our in-house library of CYP51 inhibitors against a fungus Cryptococcus neoformans (cryptococcal meningitis) and two free-living pathogenic amoebas, Acanthamoeba castellanii (blinding keratitis) and Nagleria fowleri (primary amebic meningoencephalitis), as well as to test our two potent functionally irreversible inhibitors of human CYP51 in cancer cell lines and in cytomegalovirus infected human cells. Our other interests include CYP51 reaction mechanism, deciphering structure/function relations following the CYP51 catalytic cycle and CYP51 sequence evolution, either to preserve/enhance the function or to direct the host defense, and possibly to give rise to other families of cytochrome P450.

The research is supported by NIH (R01GM067871), https://reporter.nih.gov/search/xeP2dn1deUKAd9Rk5d3mVw/project-details/10077559

Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. The antifungal drug isavuconazole inhibits the replication of human cytomegalovirus (HCMV) and acts synergistically with anti-HCMV drugs. Mercorelli B, Celegato M, Luganini A, Gribaudo G, Lepesheva GI, Loregian A (2021) Antiviral Res : 105062
    › Primary publication · 33722615 (PubMed)
  2. Concerning P450 Evolution: Structural Analyses Support Bacterial Origin of Sterol 14α-Demethylases. Lamb DC, Hargrove TY, Zhao B, Wawrzak Z, Goldstone JV, Nes WD, Kelly SL, Waterman MR, Stegeman JJ, Lepesheva GI (2021) Mol Biol Evol 38(3): 952-967
    › Primary publication · 33031537 (PubMed) · PMC7947880 (PubMed Central)
  3. The Clinically Approved Antifungal Drug Posaconazole Inhibits Human Cytomegalovirus Replication. Mercorelli B, Luganini A, Celegato M, Palù G, Gribaudo G, Lepesheva GI, Loregian A (2020) Antimicrob Agents Chemother 64(10)
    › Primary publication · 32690644 (PubMed) · PMC7508619 (PubMed Central)
  4. A requirement for an active proton delivery network supports a compound I-mediated C-C bond cleavage in CYP51 catalysis. Hargrove TY, Wawrzak Z, Guengerich FP, Lepesheva GI (2020) J Biol Chem 295(29): 9998-10007
    › Primary publication · 32493730 (PubMed) · PMC7380200 (PubMed Central)
  5. A new chemotype with promise against Trypanosoma cruzi. Wang X, Cal M, Kaiser M, Buckner FS, Lepesheva GI, Sanford AG, Wallick AI, Davis PH, Vennerstrom JL (2020) Bioorg Med Chem Lett 30(1): 126778
    › Primary publication · 31706668 (PubMed) · PMC6892603 (PubMed Central)
  6. Validation of Human Sterol 14α-Demethylase (CYP51) Druggability: Structure-Guided Design, Synthesis, and Evaluation of Stoichiometric, Functionally Irreversible Inhibitors. Friggeri L, Hargrove TY, Wawrzak Z, Guengerich FP, Lepesheva GI (2019) J Med Chem 62(22): 10391-10401
    › Primary publication · 31663733 (PubMed) · PMC6881533 (PubMed Central)
  7. Successful Aspects of the Coadministration of Sterol 14α-Demethylase Inhibitor VFV and Benznidazole in Experimental Mouse Models of Chagas Disease Caused by the Drug-Resistant Strain of Trypanosoma cruzi. Guedes-da-Silva FH, Batista DDGJ, Da Silva CF, Pavão BP, Batista MM, Moreira OC, Souza LRQ, Britto C, Rachakonda G, Villalta F, Lepesheva GI, Soeiro MNC (2019) ACS Infect Dis 5(3): 365-371
    › Primary publication · 30625275 (PubMed) · PMC6408276 (PubMed Central)
  8. Sterol 14α-Demethylase Structure-Based Optimization of Drug Candidates for Human Infections with the Protozoan Trypanosomatidae. Friggeri L, Hargrove TY, Rachakonda G, Blobaum AL, Fisher P, de Oliveira GM, da Silva CF, Soeiro MNC, Nes WD, Lindsley CW, Villalta F, Guengerich FP, Lepesheva GI (2018) J Med Chem 61(23): 10910-10921
    › Primary publication · 30451500 (PubMed) · PMC6467724 (PubMed Central)
  9. Binding of a physiological substrate causes large-scale conformational reorganization in cytochrome P450 51. Hargrove TY, Wawrzak Z, Fisher PM, Child SA, Nes WD, Guengerich FP, Waterman MR, Lepesheva GI (2018) J Biol Chem 293(50): 19344-19353
    › Primary publication · 30327430 (PubMed) · PMC6302162 (PubMed Central)
  10. Sterol 14α-Demethylase Structure-Based Design of VNI (( R)- N-(1-(2,4-Dichlorophenyl)-2-(1 H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide)) Derivatives To Target Fungal Infections: Synthesis, Biological Evaluation, and Crystallographic Analysis. Friggeri L, Hargrove TY, Wawrzak Z, Blobaum AL, Rachakonda G, Lindsley CW, Villalta F, Nes WD, Botta M, Guengerich FP, Lepesheva GI (2018) J Med Chem 61(13): 5679-5691
    › Primary publication · 29894182 (PubMed) · PMC6176729 (PubMed Central)
  11. CYP51 as drug targets for fungi and protozoan parasites: past, present and future. Lepesheva GI, Friggeri L, Waterman MR (2018) Parasitology 145(14): 1820-1836
    › Primary publication · 29642960 (PubMed) · PMC6185833 (PubMed Central)
  12. A convergent, scalable and stereoselective synthesis of azole CYP51 inhibitors. Lepesheva G, Christov P, Sulikowski GA, Kim K (2017) Tetrahedron Lett 58(45): 4248-4250
    › Primary publication · 29371747 (PubMed) · PMC5777588 (PubMed Central)
  13. Antitrypanosomal and antileishmanial activity of prenyl-1,2,3-triazoles. Porta EOJ, Jäger SN, Nocito I, Lepesheva GI, Serra EC, Tekwani BL, Labadie GR (2017) Medchemcomm 8(5): 1015-1021
    › Primary publication · 28993794 (PubMed) · PMC5629980 (PubMed Central)
  14. Sterol 14α-demethylase mutation leads to amphotericin B resistance in Leishmania mexicana. Mwenechanya R, Kovářová J, Dickens NJ, Mudaliar M, Herzyk P, Vincent IM, Weidt SK, Burgess KE, Burchmore RJS, Pountain AW, Smith TK, Creek DJ, Kim DH, Lepesheva GI, Barrett MP (2017) PLoS Negl Trop Dis 11(6): e0005649
    › Primary publication · 28622334 (PubMed) · PMC5498063 (PubMed Central)
  15. Crystal Structure of the New Investigational Drug Candidate VT-1598 in Complex with Aspergillus fumigatus Sterol 14α-Demethylase Provides Insights into Its Broad-Spectrum Antifungal Activity. Hargrove TY, Garvey EP, Hoekstra WJ, Yates CM, Wawrzak Z, Rachakonda G, Villalta F, Lepesheva GI (2017) Antimicrob Agents Chemother 61(7)
    › Primary publication · 28461309 (PubMed) · PMC5487673 (PubMed Central)
  16. Structural analyses of sterol 14α-demethylase complexed with azole drugs address the molecular basis of azole-mediated inhibition of fungal sterol biosynthesis. Hargrove TY, Friggeri L, Wawrzak Z, Qi A, Hoekstra WJ, Schotzinger RJ, York JD, Guengerich FP, Lepesheva GI (2017) J Biol Chem 292(16): 6728-6743
    › Primary publication · 28258218 (PubMed) · PMC5399120 (PubMed Central)
  17. Antitrypanosomal Activity of Sterol 14α-Demethylase (CYP51) Inhibitors VNI and VFV in the Swiss Mouse Models of Chagas Disease Induced by the Trypanosoma cruzi Y Strain. Guedes-da-Silva FH, Batista DG, Da Silva CF, De Araújo JS, Pavão BP, Simões-Silva MR, Batista MM, Demarque KC, Moreira OC, Britto C, Lepesheva GI, Soeiro MN (2017) Antimicrob Agents Chemother 61(4)
    › Primary publication · 28167559 (PubMed) · PMC5365685 (PubMed Central)
  18. Human sterol 14α-demethylase as a target for anticancer chemotherapy: towards structure-aided drug design. Hargrove TY, Friggeri L, Wawrzak Z, Sivakumaran S, Yazlovitskaya EM, Hiebert SW, Guengerich FP, Waterman MR, Lepesheva GI (2016) J Lipid Res 57(8): 1552-63
    › Primary publication · 27313059 (PubMed) · PMC4959870 (PubMed Central)
  19. Clinical Candidate VT-1161's Antiparasitic Effect In Vitro, Activity in a Murine Model of Chagas Disease, and Structural Characterization in Complex with the Target Enzyme CYP51 from Trypanosoma cruzi. Hoekstra WJ, Hargrove TY, Wawrzak Z, da Gama Jaen Batista D, da Silva CF, Nefertiti AS, Rachakonda G, Schotzinger RJ, Villalta F, Soeiro Mde N, Lepesheva GI (2016) Antimicrob Agents Chemother 60(2): 1058-66
    › Primary publication · 26643331 (PubMed) · PMC4750653 (PubMed Central)
  20. Ligand tunnels in T. brucei and human CYP51: Insights for parasite-specific drug design. Yu X, Nandekar P, Mustafa G, Cojocaru V, Lepesheva GI, Wade RC (2016) Biochim Biophys Acta 1860(1 Pt A): 67-78
    › Primary publication · 26493722 (PubMed) · PMC4689311 (PubMed Central)
  21. Different Therapeutic Outcomes of Benznidazole and VNI Treatments in Different Genders in Mouse Experimental Models of Trypanosoma cruzi Infection. Guedes-da-Silva FH, Batista DG, da Silva CF, Meuser MB, Simões-Silva MR, de Araújo JS, Ferreira CG, Moreira OC, Britto C, Lepesheva GI, Soeiro Mde N (2015) Antimicrob Agents Chemother 59(12): 7564-70
    › Primary publication · 26416857 (PubMed) · PMC4649169 (PubMed Central)
  22. Structure-Functional Characterization of Cytochrome P450 Sterol 14α-Demethylase (CYP51B) from Aspergillus fumigatus and Molecular Basis for the Development of Antifungal Drugs. Hargrove TY, Wawrzak Z, Lamb DC, Guengerich FP, Lepesheva GI (2015) J Biol Chem 290(39): 23916-34
    › Primary publication · 26269599 (PubMed) · PMC4583043 (PubMed Central)
  23. VFV as a New Effective CYP51 Structure-Derived Drug Candidate for Chagas Disease and Visceral Leishmaniasis. Lepesheva GI, Hargrove TY, Rachakonda G, Wawrzak Z, Pomel S, Cojean S, Nde PN, Nes WD, Locuson CW, Calcutt MW, Waterman MR, Daniels JS, Loiseau PM, Villalta F (2015) J Infect Dis 212(9): 1439-48
    › Primary publication · 25883390 (PubMed) · PMC4601915 (PubMed Central)
  24. Dynamics of CYP51: implications for function and inhibitor design. Yu X, Cojocaru V, Mustafa G, Salo-Ahen OM, Lepesheva GI, Wade RC (2015) J Mol Recognit 28(2): 59-73
    › Primary publication · 25601796 (PubMed) · PMC4337246 (PubMed Central)
  25. Novel 3-nitrotriazole-based amides and carbinols as bifunctional antichagasic agents. Papadopoulou MV, Bloomer WD, Lepesheva GI, Rosenzweig HS, Kaiser M, Aguilera-Venegas B, Wilkinson SR, Chatelain E, Ioset JR (2015) J Med Chem 58(3): 1307-19
    › Primary publication · 25580906 (PubMed) · PMC4337820 (PubMed Central)
  26. Sequence variation in CYP51A from the Y strain of Trypanosoma cruzi alters its sensitivity to inhibition. Cherkesova TS, Hargrove TY, Vanrell MC, Ges I, Usanov SA, Romano PS, Lepesheva GI (2014) FEBS Lett 588(21): 3878-85
    › Primary publication · 25217832 (PubMed) · PMC4252588 (PubMed Central)
  27. Structural basis for rational design of inhibitors targeting Trypanosoma cruzi sterol 14α-demethylase: two regions of the enzyme molecule potentiate its inhibition. Friggeri L, Hargrove TY, Rachakonda G, Williams AD, Wawrzak Z, Di Santo R, De Vita D, Waterman MR, Tortorella S, Villalta F, Lepesheva GI (2014) J Med Chem 57(15): 6704-17
    › Primary publication · 25033013 (PubMed) · PMC4136671 (PubMed Central)
  28. Dialkylimidazole inhibitors of Trypanosoma cruzi sterol 14α-demethylase as anti-Chagas disease agents. Suryadevara PK, Racherla KK, Olepu S, Norcross NR, Tatipaka HB, Arif JA, Planer JD, Lepesheva GI, Verlinde CL, Buckner FS, Gelb MH (2013) Bioorg Med Chem Lett 23(23): 6492-9
    › Primary publication · 24120539 (PubMed) · PMC4111244 (PubMed Central)
  29. Design or screening of drugs for the treatment of Chagas disease: what shows the most promise? Lepesheva GI (2013) Expert Opin Drug Discov 8(12): 1479-89
    › Primary publication · 24079515 (PubMed) · PMC3867292 (PubMed Central)
  30. Complexes of Trypanosoma cruzi sterol 14α-demethylase (CYP51) with two pyridine-based drug candidates for Chagas disease: structural basis for pathogen selectivity. Hargrove TY, Wawrzak Z, Alexander PW, Chaplin JH, Keenan M, Charman SA, Perez CJ, Waterman MR, Chatelain E, Lepesheva GI (2013) J Biol Chem 288(44): 31602-15
    › Primary publication · 24047900 (PubMed) · PMC3814756 (PubMed Central)
  31. In vitro and in vivo studies of the antiparasitic activity of sterol 14α-demethylase (CYP51) inhibitor VNI against drug-resistant strains of Trypanosoma cruzi. Soeiro Mde N, de Souza EM, da Silva CF, Batista Dda G, Batista MM, Pavão BP, Araújo JS, Aiub CA, da Silva PB, Lionel J, Britto C, Kim K, Sulikowski G, Hargrove TY, Waterman MR, Lepesheva GI (2013) Antimicrob Agents Chemother 57(9): 4151-63
    › Primary publication · 23774435 (PubMed) · PMC3754355 (PubMed Central)
  32. CYP51 structures and structure-based development of novel, pathogen-specific inhibitory scaffolds. Hargrove TY, Kim K, de Nazaré Correia Soeiro M, da Silva CF, Batista DD, Batista MM, Yazlovitskaya EM, Waterman MR, Sulikowski GA, Lepesheva GI (2012) Int J Parasitol Drugs Drug Resist : 178-186
    › Primary publication · 23504044 (PubMed) · PMC3596085 (PubMed Central)
  33. Antitrypanosomal lead discovery: identification of a ligand-efficient inhibitor of Trypanosoma cruzi CYP51 and parasite growth. Andriani G, Amata E, Beatty J, Clements Z, Coffey BJ, Courtemanche G, Devine W, Erath J, Juda CE, Wawrzak Z, Wood JT, Lepesheva GI, Rodriguez A, Pollastri MP (2013) J Med Chem 56(6): 2556-67
    › Primary publication · 23448316 (PubMed) · PMC3612894 (PubMed Central)
  34. VNI cures acute and chronic experimental Chagas disease. Villalta F, Dobish MC, Nde PN, Kleshchenko YY, Hargrove TY, Johnson CA, Waterman MR, Johnston JN, Lepesheva GI (2013) J Infect Dis 208(3): 504-11
    › Primary publication · 23372180 (PubMed) · PMC3698996 (PubMed Central)
  35. Organocatalytic, enantioselective synthesis of VNI: a robust therapeutic development platform for Chagas, a neglected tropical disease. Dobish MC, Villalta F, Waterman MR, Lepesheva GI, Johnston JN (2012) Org Lett 14(24): 6322-5
    › Primary publication · 23214987 (PubMed) · PMC3528807 (PubMed Central)
  36. Pharmacological characterization, structural studies, and in vivo activities of anti-Chagas disease lead compounds derived from tipifarnib. Buckner FS, Bahia MT, Suryadevara PK, White KL, Shackleford DM, Chennamaneni NK, Hulverson MA, Laydbak JU, Chatelain E, Scandale I, Verlinde CL, Charman SA, Lepesheva GI, Gelb MH (2012) Antimicrob Agents Chemother 56(9): 4914-21
    › Primary publication · 22777048 (PubMed) · PMC3421879 (PubMed Central)
  37. Novel sterol metabolic network of Trypanosoma brucei procyclic and bloodstream forms. Nes CR, Singha UK, Liu J, Ganapathy K, Villalta F, Waterman MR, Lepesheva GI, Chaudhuri M, Nes WD (2012) Biochem J 443(1): 267-77
    › Primary publication · 22176028 (PubMed) · PMC3491665 (PubMed Central)
  38. Structural complex of sterol 14α-demethylase (CYP51) with 14α-methylenecyclopropyl-Delta7-24, 25-dihydrolanosterol. Hargrove TY, Wawrzak Z, Liu J, Waterman MR, Nes WD, Lepesheva GI (2012) J Lipid Res 53(2): 311-20
    › Primary publication · 22135275 (PubMed) · PMC3269163 (PubMed Central)
  39. Targeting Trypanosoma cruzi sterol 14α-demethylase (CYP51). Lepesheva GI, Villalta F, Waterman MR (2011) Adv Parasitol : 65-87
    › Primary publication · 21820552 (PubMed) · PMC3488290 (PubMed Central)
  40. Substrate preferences and catalytic parameters determined by structural characteristics of sterol 14alpha-demethylase (CYP51) from Leishmania infantum. Hargrove TY, Wawrzak Z, Liu J, Nes WD, Waterman MR, Lepesheva GI (2011) J Biol Chem 286(30): 26838-48
    › Primary publication · 21632531 (PubMed) · PMC3143644 (PubMed Central)
  41. Sterol 14alpha-demethylase (CYP51) as a therapeutic target for human trypanosomiasis and leishmaniasis. Lepesheva GI, Waterman MR (2011) Curr Top Med Chem 11(16): 2060-71
    › Primary publication · 21619513 (PubMed) · PMC3391166 (PubMed Central)
  42. Structural basis for conservation in the CYP51 family. Lepesheva GI, Waterman MR (2011) Biochim Biophys Acta 1814(1): 88-93
    › Primary publication · 20547249 (PubMed) · PMC2962772 (PubMed Central)
  43. Structural insights into inhibition of sterol 14alpha-demethylase in the human pathogen Trypanosoma cruzi. Lepesheva GI, Hargrove TY, Anderson S, Kleshchenko Y, Furtak V, Wawrzak Z, Villalta F, Waterman MR (2010) J Biol Chem 285(33): 25582-90
    › Primary publication · 20530488 (PubMed) · PMC2919122 (PubMed Central)
  44. Crystal structures of Trypanosoma brucei sterol 14alpha-demethylase and implications for selective treatment of human infections. Lepesheva GI, Park HW, Hargrove TY, Vanhollebeke B, Wawrzak Z, Harp JM, Sundaramoorthy M, Nes WD, Pays E, Chaudhuri M, Villalta F, Waterman MR (2010) J Biol Chem 285(3): 1773-80
    › Primary publication · 19923211 (PubMed) · PMC2804335 (PubMed Central)
  45. The first virally encoded cytochrome p450. Lamb DC, Lei L, Warrilow AG, Lepesheva GI, Mullins JG, Waterman MR, Kelly SL (2009) J Virol 83(16): 8266-9
    › Primary publication · 19515774 (PubMed) · PMC2715754 (PubMed Central)
  46. Indomethacin amides as a novel molecular scaffold for targeting Trypanosoma cruzi sterol 14alpha-demethylase. Konkle ME, Hargrove TY, Kleshchenko YY, von Kries JP, Ridenour W, Uddin MJ, Caprioli RM, Marnett LJ, Nes WD, Villalta F, Waterman MR, Lepesheva GI (2009) J Med Chem 52(9): 2846-53
    › Primary publication · 19354253 (PubMed) · PMC2744100 (PubMed Central)
  47. Rational modification of a candidate cancer drug for use against Chagas disease. Kraus JM, Verlinde CL, Karimi M, Lepesheva GI, Gelb MH, Buckner FS (2009) J Med Chem 52(6): 1639-47
    › Primary publication · 19239254 (PubMed) · PMC2715367 (PubMed Central)
  48. CYP51: A major drug target in the cytochrome P450 superfamily. Lepesheva GI, Hargrove TY, Kleshchenko Y, Nes WD, Villalta F, Waterman MR (2008) Lipids 43(12): 1117-25
    › Primary publication · 18769951 (PubMed) · PMC2715142 (PubMed Central)
  49. Sterol 14alpha-demethylase as a potential target for antitrypanosomal therapy: enzyme inhibition and parasite cell growth. Lepesheva GI, Ott RD, Hargrove TY, Kleshchenko YY, Schuster I, Nes WD, Hill GC, Villalta F, Waterman MR (2007) Chem Biol 14(11): 1283-93
    › Primary publication · 18022567 (PubMed) · PMC2324070 (PubMed Central)
  50. Conformational dynamics in the F/G segment of CYP51 from Mycobacterium tuberculosis monitored by FRET. Lepesheva GI, Seliskar M, Knutson CG, Stourman NV, Rozman D, Waterman MR (2007) Arch Biochem Biophys 464(2): 221-7
    › Primary publication · 17585868 (PubMed) · PMC3042880 (PubMed Central)
  51. Biodiversity of CYP51 in trypanosomes. Lepesheva GI, Hargrove TY, Ott RD, Nes WD, Waterman MR (2006) Biochem Soc Trans 34(Pt 6): 1161-4
    › Primary publication · 17073776 (PubMed)
  52. Role of C-terminal sequence of cytochrome P450scc in folding and functional activity. Strushkevich NV, Harnastai IN, Lepesheva GI, Usanov SA (2006) Biochemistry (Mosc) 71(9): 1027-34
    › Primary publication · 17009958 (PubMed)
  53. Sterol 14alpha-demethylase cytochrome P450 (CYP51), a P450 in all biological kingdoms. Lepesheva GI, Waterman MR (2007) Biochim Biophys Acta 1770(3): 467-77
    › Primary publication · 16963187 (PubMed) · PMC2324071 (PubMed Central)
  54. Mechanistic analysis of a multiple product sterol methyltransferase implicated in ergosterol biosynthesis in Trypanosoma brucei. Zhou W, Lepesheva GI, Waterman MR, Nes WD (2006) J Biol Chem 281(10): 6290-6
    › Primary publication · 16414960 (PubMed)
  55. A second FMN binding site in yeast NADPH-cytochrome P450 reductase suggests a mechanism of electron transfer by diflavin reductases. Lamb DC, Kim Y, Yermalitskaya LV, Yermalitsky VN, Lepesheva GI, Kelly SL, Waterman MR, Podust LM (2006) Structure 14(1): 51-61
    › Primary publication · 16407065 (PubMed)
  56. CYP51 from Trypanosoma cruzi: a phyla-specific residue in the B' helix defines substrate preferences of sterol 14alpha-demethylase. Lepesheva GI, Zaitseva NG, Nes WD, Zhou W, Arase M, Liu J, Hill GC, Waterman MR (2006) J Biol Chem 281(6): 3577-85
    › Primary publication · 16321980 (PubMed)
  57. Sterol 14 alpha-demethylase, an abundant and essential mixed-function oxidase. Waterman MR, Lepesheva GI (2005) Biochem Biophys Res Commun 338(1): 418-22
    › Primary publication · 16153595 (PubMed)
  58. Role of positively charged residues lys267, lys270, and arg411 of cytochrome p450scc (CYP11A1) in interaction with adrenodoxin. Strushkevich NV, Azeva TN, Lepesheva GI, Usanov SA (2005) Biochemistry (Mosc) 70(6): 664-71
    › Primary publication · 16038609 (PubMed)
  59. Estriol bound and ligand-free structures of sterol 14alpha-demethylase. Podust LM, Yermalitskaya LV, Lepesheva GI, Podust VN, Dalmasso EA, Waterman MR (2004) Structure 12(11): 1937-45
    › Primary publication · 15530358 (PubMed)
  60. Fluconazole binding and sterol demethylation in three CYP51 isoforms indicate differences in active site topology. Bellamine A, Lepesheva GI, Waterman MR (2004) J Lipid Res 45(11): 2000-7
    › Primary publication · 15314102 (PubMed)
  61. CYP51 from Trypanosoma brucei is obtusifoliol-specific. Lepesheva GI, Nes WD, Zhou W, Hill GC, Waterman MR (2004) Biochemistry 43(33): 10789-99
    › Primary publication · 15311940 (PubMed)
  62. CYP51--the omnipotent P450. Lepesheva GI, Waterman MR (2004) Mol Cell Endocrinol 215(1-2): 165-70
    › Primary publication · 15026190 (PubMed)
  63. Conservation in the CYP51 family. Role of the B' helix/BC loop and helices F and G in enzymatic function. Lepesheva GI, Virus C, Waterman MR (2003) Biochemistry 42(30): 9091-101
    › Primary publication · 12885242 (PubMed)
  64. Probing the interaction of bovine cytochrome P450scc (CYP11A1) with adrenodoxin: evaluating site-directed mutations by molecular modeling. Usanov SA, Graham SE, Lepesheva GI, Azeva TN, Strushkevich NV, Gilep AA, Estabrook RW, Peterson JA (2002) Biochemistry 41(26): 8310-20
    › Primary publication · 12081479 (PubMed)
  65. 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. Azeva TN, Gilep AA, Lepesheva GI, Strushkevich NV, Usanov SA (2001) Biochemistry (Mosc) 66(5): 564-75
    › Primary publication · 11405894 (PubMed)
  66. Folding requirements are different between sterol 14alpha-demethylase (CYP51) from Mycobacterium tuberculosis and human or fungal orthologs. Lepesheva GI, Podust LM, Bellamine A, Waterman MR (2001) J Biol Chem 276(30): 28413-20
    › Primary publication · 11373285 (PubMed)
  67. Site-directed mutagenesis of cytochrome P450scc (CYP11A1). Effect of lysine residue substitution on its structural and functional properties. Lepesheva GI, Azeva TN, Strushkevich NV, Gilep AA, Usanov SA (2000) Biochemistry (Mosc) 65(12): 1409-18
    › Primary publication · 11173513 (PubMed)
  68. Conformational dynamics and molecular interaction reactions of recombinant cytochrome p450scc (CYP11A1) detected by fluorescence energy transfer. Lepesheva GI, Strushkevich NV, Usanov SA (1999) Biochim Biophys Acta 1434(1): 31-43
    › Primary publication · 10556557 (PubMed)
  69. Dynamics and functional activity of cytochrome P450scc selectively labeled with fluorescein isothiocyanate. Lepesheva GI, Usanov SA (1997) Biochemistry (Mosc) 62(6): 648-56
    › Primary publication · 9324423 (PubMed)
  70. [The use of selective chemical modification of cytochrome P450scc (CYPXIA1) with fluorescein isothiocyanate for evaluation of intramolecular distances and conformational changes by fluorescent resonance energy transfer]. Lepesheva GI, Usanov SA (1996) Biokhimiia 61(8): 1395-407
    › Primary publication · 8962914 (PubMed)
  71. [IgG, modified with coproporphyrin I and the possibility of direct measurement of the antigen-antibody complex]. Lepesheva GI, Turko IV, Shestakov VL, Chashchin VL (1993) Biokhimiia 58(6): 938-43
    › Primary publication · 8364116 (PubMed)
  72. [Direct detection of an antigen in immunoglobulin G Langmuir-Blodgett films based on a surface plasma resonance method and in a piezoelectric system]. Lepesheva GI, Turko IV, Ges' IA, Chashchin VL (1994) Biokhimiia 59(7): 939-45
    › Primary publication · 7948419 (PubMed)
  73. [The use of biotin-streptavidin systems for enhancing the parameters of immunometric analysis]. Lepesheva GI, Martsev SP (1990) Zh Mikrobiol Epidemiol Immunobiol (10): 121-5
    › Primary publication · 2075757 (PubMed)
  74. [Modification of a disulfide in the hinge region of rabbit IgG and study of the interaction of polyvalent ferritin antigen, protein A, and anti-IgG]. Lepesheva GI, Martsev SP (1992) Biokhimiia 57(7): 1089-99
    › Primary publication · 1391214 (PubMed)