title: Three-dimensional model of lanosterol 14 alpha-demethylase from Cryptococcus neoformans: active-site characterization and insights into azole binding.
abstract: Cryptococcus neoformans is one of the most important causes of life-threatening fungal infections in immunocompromised patients. Lanosterol 14 alpha-demethylase (CYP51) is the target of azole antifungal agents. This study describes, for the first time, the 3-dimensional model of CYP51 from Cryptococcus neoformans (CnCYP51). The model was further refined by energy minimization and molecular-dynamics simulations. The active site of CnCYP51 was well characterized by multiple-copy simultaneous-search calculations, and four functional regions important for rational drug design were identified. The mode of binding of the natural substrate and azole antifungal agents with CnCYP51 was identified by flexible molecular docking. A G484S substitution mechanism for azole resistance in CnCYP51, which might be important for the conformation of the heme environment, is suggested.
authors.affiliation: School of Pharmacy, Military Key Laboratory of Medicinal Chemistry, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
authors.forename: Chunquan
authors.initials: C
authors.lastname: Sheng
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Miao
authors.forename: Haitao
authors.initials: H
authors.lastname: Ji
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Yao
authors.forename: Wenya
authors.initials: W
authors.lastname: Wang
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Che
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Dong
authors.forename: Jiaguo
authors.initials: J
authors.lastname: Lü
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.forename: Wannian
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000595:Amino Acid Sequence; D000935:Antifungal Agents / Q000737:chemistry* / Q000378:metabolism*; D001393:Azoles / Q000737:chemistry* / Q000378:metabolism*; D020134:Catalytic Domain; D003198:Computer Simulation; D003455:Cryptococcus neoformans / Q000201:enzymology*; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism*; D005656:Fungal Proteins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D058886:Sterol 14-Demethylase; D013816:Thermodynamics
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D005656:Fungal Proteins; D003577:Cytochrome P-450 Enzyme System; D058886:Sterol 14-Demethylase