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Antimicrobial Agents and Chemotherapy, August 2009, p. 3487-3495, Vol. 53, No. 8
0066-4804/09/$08.00+0     doi:10.1128/AAC.01630-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Three-Dimensional Model of Lanosterol 14{alpha}-Demethylase from Cryptococcus neoformans: Active-Site Characterization and Insights into Azole Binding {triangledown} ,{dagger}

Chunquan Sheng,1 Zhenyuan Miao,1 Haitao Ji,2 Jianzhong Yao,1 Wenya Wang,1 Xiaoying Che,1 Guoqiang Dong,1 Jiaguo Lü,1 Wei Guo,1 and Wannian Zhang1*

School of Pharmacy, Military Key Laboratory of Medicinal Chemistry, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China,1 Department of Chemistry, Department of Biochemistry, Molecular Biology, and Cell Biology, and Center for Drug Discovery and Chemical Biology, Northwestern University, Evanston, Illinois 60208-31132

Received 11 December 2008/ Returned for modification 4 March 2009/ Accepted 17 May 2009

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.

* Corresponding author. Mailing address: School of Pharmacy, Military Key Laboratory of Medicinal Chemistry, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China. Phone and fax: 86-21-81871243. E-mail: zhangwnk{at}hotmail.com

{triangledown} Published ahead of print on 26 May 2009.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, August 2009, p. 3487-3495, Vol. 53, No. 8
0066-4804/09/$08.00+0     doi:10.1128/AAC.01630-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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