Dynamics of CYP51: Implications for function and inhibitor design

Journal of Molecular Recognition

Volumn 28, Issue 2, 2015, Pages 59-73

  Yu, Xiaofeng ^a   Cojocaru, Vlad ^b   Mustafa, Ghulam ^a   Salo Ahen, Outi M H ^c   Lepesheva, Galina I ^d   Wade, Rebecca C ^a,e  

^a HEIDELBERG INSTITUTE FOR THEORETICAL STUDIES   (Germany)

^b MAX PLANCK INSTITUTE FOR MOLECULAR BIOMEDICINE   (Germany)

^c ÅBO AKADEMI UNIVERSITY   (Finland)

^d VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

^e UNIVERSITY OF HEIDELBERG   (Germany)

Author keywords

CYP51; Cytochrome P450; Heme propionate groups; Ligand tunnel; Membrane bound protein; Molecular dynamics simulation; Protein dynamics; Sterol 14 demethylase

Indexed keywords

EUKARYOTA; TRYPANOSOMA BRUCEI;

CYP2C9 PROTEIN, HUMAN; CYP51A1 PROTEIN, HUMAN; CYTOCHROME P450 2C9; PROTOZOAL PROTEIN; SOLVENT; STEROL 14ALPHA DEMETHYLASE;

CHEMISTRY; COMPARATIVE STUDY; DRUG DESIGN; ENZYME ACTIVE SITE; ENZYME SPECIFICITY; ENZYMOLOGY; HUMAN; HYDROGEN BOND; METABOLISM; MOLECULAR DYNAMICS; PROTEIN SECONDARY STRUCTURE; TRYPANOSOMA BRUCEI BRUCEI; X RAY CRYSTALLOGRAPHY;

CATALYTIC DOMAIN; CRYSTALLOGRAPHY, X-RAY; CYTOCHROME P-450 CYP2C9; DRUG DESIGN; HUMANS; HYDROGEN BONDING; MOLECULAR DYNAMICS SIMULATION; PROTEIN STRUCTURE, SECONDARY; PROTOZOAN PROTEINS; SOLVENTS; STEROL 14-DEMETHYLASE; SUBSTRATE SPECIFICITY; TRYPANOSOMA BRUCEI BRUCEI;

EID: 84921771494     PISSN: 09523499     EISSN: 10991352     Source Type: Journal    
DOI: 10.1002/jmr.2412     Document Type: Article

References (69)

1. Allen WJ, Lemkul JA, Bevan DR. 2009. GridMAT-MD: a grid-based membrane analysis tool for use with molecular dynamics. J. Comput. Chem. 30: 1952-8.
2. 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. Antitrypanosomal lead discovery: identification of a ligand-efficient inhibitor of Trypanosoma cruzi CYP51 and parasite growth. J. Med. Chem. 56: 2556-67.
3. Aoyama Y, Noshiro M, Gotoh O, Imaoka S, Funae Y. 1996. Sterol 14-Demethylase P450 ( P45014DM ∗) Is One of the Most Ancient and Conserved P450 Species. J. Biochem. 933: 926-933.
4. Bayburt TH, Sligar SG. 2002. Single-molecule height measurements on microsomal cytochrome P450 in nanometer-scale phospholipid bilayer disks. Proc. Natl. Acad. Sci. U. S. A. 99: 6725-30.
5. Baylon JL, Lenov IL, Sligar SG, Tajkhorshid E. 2013. Characterizing the membrane-bound state of cytochrome P450 3A4: structure, depth of insertion, and orientation. J. Am. Chem. Soc. 135: 8542-51.
6. Bayly CI, Cieplak P, Cornell W, Kollman PA. 1993. A well-behaved electrostatic potential based method using charge restraints for deriving atomic charges: the RESP model. J. Phys. Chem. 97: 10269-10280.
7. Berendsen HJC, van der Spoel D, van Drunen R. 1995. GROMACS: A message-passing parallel molecular dynamics implementation. Comput. Phys. Commun. 91: 43-56.
8. Berka K, Hendrychová T, Anzenbacher P, Otyepka M. 2011. Membrane position of ibuprofen agrees with suggested access path entrance to cytochrome P450 2C9 active site. J. Phys. Chem. A 115: 11248-55.
9. Berka K, Paloncýová M, Anzenbacher P, Otyepka M. 2013. Behavior of Human Cytochromes P450 on Lipid Membranes. J. Phys. Chem. B 117: 11556-11564.
10. Black SD, Martin ST, Smith CA. 1994. Membrane Topology of Liver Microsomal Cytochrome P450 2B4 Determined via Monoclonal Antibodies Directed to the Halt-Transfer Signal. Biochemistry 33: 6945-6951.
11. Case DA, Darden TA, Cheatham, III TE, Simmerling CL, Wang J, Duke RE, Luo R, Walker RC, Zhang W, Merz KM, Reberts B, Hayik S, Roitberg A, Seabra G, Swails J, Goetz AW, Kolossvary I, Wong KF, Paesani F, Vanicek J, Wolf RM, Liu J, Wu X, Brozell SR, Steinbrecher T, Gohlke H, Cai Q, Ye X, Wang J, Hsieh M-J, Cui G, Roe DR, Mathews DH, Seetin MG, Salomon-Ferrer R, Sagui C, Babin V, Luchko T, Gusarov S, Kovalenko A, Kollman PA. 2012. Amber 12. San Francisco: University of Califonia.
12. Case DA, Darden TA, Cheatham, III TE, Simmerling CL, Wang J, Duke RE, Luo R, Walker RC, Zhang W, Merz KM, Reberts B, Wang B, Hayik S, Roitberg A, Seabra G, Kolossvary I, Wong KM, Paesani F, Vanicek J, Liu J, Wu X, Brozell SR, Steinbrecher T, Gohlke H, CaiQ, Ye X, Wang J, Hsieh M-J, Cui G, Roe DR, Mathews DH, Seetin MG, Sagui C, Babin V, Luchko T, Gusarov S, Kovalenko A, Kollman PA. 2010. Amber 11. San Francisco: University of Califonia.
13. Chen Z, Ost TWB, Schelvis JPM. 2004. Phe393 mutants of cytochrome P450 BM3 with modified heme redox potentials have altered heme vinyl and propionate conformations. Biochemistry 43: 1798-808.
14. Chovancova E, Pavelka A, Benes P, Strnad O, Brezovsky J, Kozlikova B, Gora A, Sustr V, Klvana M, Medek P, Biedermannova L, Sochor J, Damborsky J. 2012. CAVER 3.0: a tool for the analysis of transport pathways in dynamic protein structures. PLoS Comput. Biol. 8: e1002708.
15. Cojocaru V, Balali-Mood K, Sansom MSP, Wade RC. 2011. Structure and dynamics of the membrane-bound cytochrome P450 2C9. PLoS Comput. Biol. 7: e1002152.
16. Cojocaru V, Winn PJ, Wade RC. 2007. The ins and outs of cytochrome P450s. Biochim. Biophys. Acta 1770: 390-401.
17. Denisov IG, Shih AY, Sligar SG. 2012. Structural differences between soluble and membrane bound cytochrome P450s. J. Inorg. Biochem. 108: 150-8.
18. Dolinsky TJ, Nielsen JE, McCammon JA, Baker NA. 2004. PDB2PQR: an automated pipeline for the setup of Poisson-Boltzmann electrostatics calculations. Nucleic Acids Res. 32: W665-7.
19. Dupradeau F-Y, Pigache A, Zaffran T, Savineau C, Lelong R, Grivel N, Lelong D, Rosanski W, Cieplak P. 2010. The R.E.D. tools: advances in RESP and ESP charge derivation and force field library building. Phys. Chem. Chem. Phys. 12: 7821-39.
20. Frey B, David D. 1987. Determination of the Membrane Topology of the Phenobarbital-inducible Rat Liver Cytochrome P-450 Isoenzyme PB-4 Using Site-specific Antibodies. J. Cell Biol. 104: 209-219.
21. Gotoh O. 1992. Substrate Recognition Sites in Cytochrome P450 Family 2 (CYP2) Proteins Inferred from Comparative Analyses of Amino Acid and Coding Nucleotide Sequences. J. Biol. Chem. 267: 83-90.
22. Guallar V, Baik M, Lippard SJ, Friesner RA. 2003. Peripheral heme substituents control the hydrogen-atom abstraction chemistry in cytochromes P450. Proc. Natl. Acad. Sci. U. S. A. 100: 6998-7002.
23. Haider S, Islam B, D'Atri V, Sgobba M, Poojari C, Sun L, Yuen T, Zaidi M, New MI. 2013. Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia. Proc. Natl. Acad. Sci. U. S. A. 110: 2605-10.
24. Hargrove TY, Kim K, de Nazaré Correia Soeiro M, da Silva CF, da Gama Jaen Batista D, Batista MM, Yazlovitskaya EM, Waterman MR, Sulikowski GA, Lepesheva GI. 2012a. CYP51 structures and structure-based development of novel, pathogen-specific inhibitory scaffolds. Int. J. Parasitol. Drugs Drug Resist. 2: 178-186.
25. Hargrove TY, Wawrzak Z, Liu J, Nes WD, Waterman MR, Lepesheva GI. 2011. Substrate preferences and catalytic parameters determined by structural characteristics of sterol 14alpha-demethylase (CYP51) from Leishmania infantum. J. Biol. Chem. 286: 26838-48.
26. Hargrove TY, Wawrzak Z, Liu J, Waterman MR, Nes WD, Lepesheva GI. 2012b. Structural complex of sterol 14α-demethylase (CYP51) with 14α-methylenecyclopropyl-Delta7-24, 25-dihydrolanosterol. J. Lipid Res. 53: 311-20.
27. Harris DL, Park J-Y, Gruenke L, Waskell L. 2004. Theoretical study of the ligand-CYP2B4 complexes: effect of structure on binding free energies and heme spin state. Proteins 55: 895-914.
28. Hasemann CA, Kurumbail RG, Boddupalli SS, Peterson JA, Deisenhofer J. 1995. Structure and function of cytochromes P450:a comparative analysis of three crystal structures. Structure 3: 41-62.
29. Headlam M. 2003. The F-G loop region of cytochrome P450scc (CYP11A1) interacts with the phospholipid membrane. Biochim. Biophys. Acta, Biomemb. 1617: 96-108.
30. Hendrychova T, Berka K, Navratilova V, Anzenbacher P, Otyepka M. 2012. Dynamics and hydration of the active sites of mammalian cytochromes P450 probed by molecular dynamics simulations. Curr. Drug Metab. 13: 177-89.
31. Hess B, Kutzner C, van der Spoel D, Lindahl E. 2008. GROMACS 4: Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation. J. Chem. Theory Comput. 4: 435-447.
32. Hornak V, Abel R, Okur A, Strockbine B, Roitberg A, Simmerling C. 2006. Comparison of multiple Amber force fields and development of improved protein backbone parameters. Proteins 65: 712-25.
33. Humphrey W, Dalke A, Schulten K. 1996. VMD: Visual molecular dynamics. J. Mol. Graph. 14: 33-38.
34. Jójárt B, Martinek TA. 2007. Performance of the general amber force field in modeling aqueous POPC membrane bilayers. J. Comput. Chem. 28: 2051-8.
35. Jorgensen WL, Madura JD. 1983. Quantum and statistical mechanical studies of liquids. 25. Solvation and conformation of methanol in water. J. Am. Chem. Soc. 105: 1407-1413.
36. Lepesheva GI, Hargrove TY, Anderson S, Kleshchenko Y, Furtak V, Wawrzak Z, Villalta F, Waterman MR. 2010a. Structural insights into inhibition of sterol 14alpha-demethylase in the human pathogen Trypanosoma cruzi. J. Biol. Chem. 285: 25582-90.
37. Lepesheva GI, Hargrove TY, Kleshchenko Y, Nes WD, Villalta F, Waterman MR. 2008. CYP51: A major drug target in the cytochrome P450 superfamily. Lipids 43: 1117-25.
38. Lepesheva GI, Park H-W, Hargrove TY, Vanhollebeke B, Wawrzak Z, Harp JM, Sundaramoorthy M, Nes WD, Pays E, Chaudhuri M, Villalta F, Waterman MR. 2010b. Crystal structures of Trypanosoma brucei sterol 14alpha-demethylase and implications for selective treatment of human infections. J. Biol. Chem. 285: 1773-80.
39. Lepesheva GI, Waterman MR. 2004. CYP51-the omnipotent P450. Mol. Cell. Endocrinol. 215: 165-70.
40. Lepesheva GI, Waterman MR. 2011. Sterol 14alpha-Demethylase (CYP51) as a Therapeutic Target for Human Trypanosomiasis and Leishmaniasis. Curr. Top. Med. Chem. 11: 2060-2071.
41. Lindahl E, Hess B, van der Spoel D. 2001. GROMACS 3.0: a package for molecular simulation and trajectory analysis. J. Mol. Model. 7: 306-317.
42. Lomize MA, Lomize AL, Pogozheva ID, Mosberg HI. 2006. OPM: orientations of proteins in membranes database. Bioinformatics 22: 623-5.
43. Marrink S-J, de Vries AH, Mark AE. 2004. Coarse Grained Model for Semiquantitative Lipid Simulations. J. Phys. Chem. B 108: 750-760.
44. Marrink S-J, Risselada HJ, Yefimov S, Tieleman DP, de Vries AH. 2007. The MARTINI force field: coarse grained model for biomolecular simulations. J. Phys. Chem. B 111: 7812-24.
45. Miao Y, Baudry J. 2011. Active-site hydration and water diffusion in cytochrome P450cam: a highly dynamic process. Biophys. J. 101: 1493-503.
46. Miao Y, Yi Z, Cantrell C, Glass DC, Baudry J, Jain N, Smith JC. 2012. Coupled flexibility change in cytochrome P450cam substrate binding determined by neutron scattering, NMR, and molecular dynamics simulation. Biophys. J. 103: 2167-76.
47. Monk BC, Tomasiak TM, Keniya MV, Huschmann FU, Tyndall JD, O'Connell JD, Cannon RD, McDonald JG, Rodriguez A, Finer-Moore JS, Stroud RM. 2014. Architecture of a single membrane spanning cytochrome P450 suggests constraints that orient the catalytic domain relative to a bilayer. Proc. Natl. Acad. Sci. 111: 3865-3870.
48. Monticelli L, Kandasamy SK, Periole X, Larson RG, Tieleman DP, Marrink SJ. 2008. The MARTINI Coarse-Grained Force Field: Extension to Proteins. J. Chem. Theory Comput. 4: 819-834.
49. Nelson DR. 1999. Cytochrome P450 and the individuality of species. Arch. Biochem. Biophys. 369: 1-10.
50. Ohta Y, Kawato S, Tagashira H, Takemori S, Kominami S. 1992. Dynamic structures of adrenocortical cytochrome P-450 in proteoliposomes and microsomes: protein rotation study. Biochemistry 31: 12680-12687.
51. Ozalp C, Szczesna-Skorupa E, Kemper B. 2006. Identification of membrane-contacting loops of the catalytic domain of cytochrome P450 2C2 by tryptophan fluorescence scanning. Biochemistry 45: 4629-37.
52. Pei J, Kim B-H, Grishin NV. 2008. PROMALS3D: a tool for multiple protein sequence and structure alignments. Nucleic Acids Res. 36: 2295-300.
53. Periole X, Cavalli M, Marrink S-J, Ceruso MA. 2009. Combining an Elastic Network With a Coarse-Grained Molecular Force Field: Structure, Dynamics, and Intermolecular Recognition. J. Chem. Theory Comput. 5: 2531-2543.
54. Phillips JC, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E, Chipot C, Skeel RD, Kalé L, Schulten K. 2005. Scalable molecular dynamics with NAMD. J. Comput. Chem. 26: 1781-802.
55. Pikuleva IA. 2004. Putative F-G loop is involved in association with the membrane in P450scc (P450 11A1). Mol. Cell. Endocrinol. 215: 161-4.
56. Pronk S, Páll S, Schulz R, Larsson P, Bjelkmar P, Apostolov R, Shirts MR, Smith JC, Kasson PM, van der Spoel D, Hess B, Lindahl E. 2013. GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics 29: 845-54.
57. Rzepiela AJ, Schäfer LV, Goga N, Risselada HJ, De Vries AH, Marrink SJ. 2010. Reconstruction of atomistic details from coarse-grained structures. J. Comput. Chem. 31: 1333-43.
58. Sali A, Blundell TL. 1993. Comparative protein modelling by satisfaction of spatial restraints. J. Mol. Biol. 234: 779-815.
59. Schrodinger LLC. 2010. The PyMOL Molecular Graphics System.
60. Sgrignani J, Magistrato A. 2012. Influence of the membrane lipophilic environment on the structure and on the substrate access/egress routes of the human aromatase enzyme. A computational study. J. Chem. Inf. Model. 52: 1595-606.
61. Stjernschantz E, van Vugt-Lussenburg BMA, Bonifacio A, de Beer SBA, van der Zwan G, Gooijer C, Commandeur JNM, Vermeulen NPE, Oostenbrink C. 2008. Structural rationalization of novel drug metabolizing mutants of cytochrome P450 BM3. Proteins 71: 336-52.
62. Van der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJC. 2005. GROMACS: fast, flexible, and free. J. Comput. Chem. 26: 1701-18.
63. Vanquelef E, Simon S, Marquant G, Garcia E, Klimerak G, Delepine JC, Cieplak P, Dupradeau F-Y. 2011. R.E.D. Server: a web service for deriving RESP and ESP charges and building force field libraries for new molecules and molecular fragments. Nucleic Acids Res. 39: W511-7.
64. Villalta F, Dobish MC, Nde PN, Kleshchenko YY, Hargrove TY, Johnson CA, Waterman MR, Johnston JN, Lepesheva GI. 2013. VNI cures acute and chronic experimental Chagas disease. J. Infect. Dis. 208: 504-11.
65. Wang J, Wang W, Kollman PA, Case DA. 2006. Automatic atom type and bond type perception in molecular mechanical calculations. J. Mol. Graph. Model. 25: 247-60.
66. Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA. 2004. Development and testing of a general amber force field. J. Comput. Chem. 25: 1157-74.
67. Yamamoto K, Gildenberg M, Ahuja S, Im S-C, Pearcy P, Waskell L, Ramamoorthy A. 2013. Probing the transmembrane structure and topology of microsomal cytochrome-p450 by solid-state NMR on temperature-resistant bicelles. Sci. Rep. 3: 2556.
68. Yoshida Y. 1988. Cytochrome P450 of fungi: primary target for azole antifungal agents. Curr. Top. Med. Mycol. 2: 388-418.
69. Yoshida Y, Aoyama Y, Noshiro M, Gotoh O. 2000. Sterol 14-demethylase P450 (CYP51) provides a breakthrough for the discussion on the evolution of cytochrome P450 gene superfamily. Biochem. Biophys. Res. Commun. 273: 799-804.