cyp51A-based mechanism of azole resistance in Aspergillus fumigatus: Illustration by a new 3D Structural Model of Aspergillus fumigatus CYP51A protein

Medical Mycology
Musang LiuWeida Liu

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 of A. 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 of A. fumigatus, respectively. In the present study, we constructed a new 3D structural model of A. 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 eventu...Continue Reading

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Citations

Sep 2, 2016·Medical Mycology Journal·Masato Tashiro, Koichi Izumikawa
Feb 22, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Masaki IkedaHitoshi Ashida
Jul 7, 2016·Antimicrobial Agents and Chemotherapy·Florencia LeonardelliGuillermo Garcia-Effron
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