title: cyp51A-based mechanism of azole resistance in Aspergillus fumigatus: Illustration by a new 3D Structural Model of Aspergillus fumigatus CYP51A protein.
abstract: Mutations of CYP51A protein (Cytochrome P450 14-α Sterol demethylase) play a central role in the azole resistance of Aspergillus fumigatus The available structural models of CYP51A protein ofA. fumigatus are built based on that of Homo sapiens and that of Mycobacterium tuberculosis, of which the amino acid homology is only 38% and 29% compared with CYP51A protein ofA. fumigatus, respectively. In the present study, we constructed a new 3D structural model ofA. fumigatus CYP51A protein based on a recently resolved crystal structure of the homologous protein in the fungus S. cerevisiae, which shares 50% amino acid homology with A. fumigatus CYP51A protein. Three azole molecules, itraconazole, voriconazole, and posaconazole, were docked to the wild-type and the mutant A. fumigatus CYP51A protein models, respectively, to illustrate the impact of cyp51A mutations to azole-resistance. We found the mutations that occurred at L98, M220, and Y431 positions would decrease the binding affinity of azoles to the CYP51A protein and therefore would reduce their inhibitory effects. Additionally, the mutations of L98 and G432 would reduce the stability of the protein, which might lead to conformational change of its binding pocket and eventually the resistance to azoles.
authors.affiliation: Department of Medical Mycology, Institute of Dermatology, Chinese Academy of Medical Science and Peking Union Medical College, Nanjing, Jiangsu, China Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, China.
authors.forename: Musang
authors.initials: M
authors.lastname: Liu
authors.affiliation: Medical School, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Zheng
authors.affiliation: Department of Medical Mycology, Institute of Dermatology, Chinese Academy of Medical Science and Peking Union Medical College, Nanjing, Jiangsu, China Georgetown University Medical Center, Department of Microbiology and Immunology, Washington DC, Washington, United States.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Medical Mycology, Institute of Dermatology, Chinese Academy of Medical Science and Peking Union Medical College, Nanjing, Jiangsu, China Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, China.
authors.forename: Hailin
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Medical Mycology, Institute of Dermatology, Chinese Academy of Medical Science and Peking Union Medical College, Nanjing, Jiangsu, China Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
authors.affiliation: The Institute of Medicinal Plant Development, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Ge
authors.affiliation: Department of Medical Mycology, Institute of Dermatology, Chinese Academy of Medical Science and Peking Union Medical College, Nanjing, Jiangsu, China Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, China liumyco@hotmail.com.
authors.forename: Weida
authors.initials: W
authors.lastname: Liu
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D001393:Azoles / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D025141:Drug Resistance, Fungal / Q000235:genetics* / Q000502:physiology; D005656:Fungal Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D062105:Molecular Docking Simulation; D009154:Mutation; D040681:Structural Homology, Protein
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D005656:Fungal Proteins; D003577:Cytochrome P-450 Enzyme System; C465526:cytochrome P-450 CYP51A, Aspergillus
keywords: Aspergillus fumigatus; CYP51A protein; azole resistance; cytochrome P450 14-α sterol demethylase; homology modeling