Structural Insights into Binding of the Antifungal Drug Fluconazole to Saccharomyces cerevisiae Lanosterol 14α-Demethylase
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Infections by fungal pathogens such as Candida albicans and Aspergillus fumigatus and their resistance to triazole drugs are major concerns. Fungal lanosterol 14α-demethylase belongs to the CYP51 class in the cytochrome P450 superfamily of enzymes. This monospanning bitopic membrane protein is involved in ergosterol biosynthesis and is the primary target of azole antifungal drugs, including fluconazole. The lack of high-resolution structural information for this drug target from fungal pathogens has been a limiting factor for the design of modified triazole drugs that will overcome resistance. Here we report the X-ray structure of full-length Saccharomyces cerevisiae lanosterol 14α-demethylase in complex with fluconazole at a resolution of 2.05 Å. This structure shows the key interactions involved in fluconazole binding and provides insight into resistance mechanisms by revealing a water-mediated hydrogen bonding network between the drug and tyrosine 140, a residue frequently found mutated to histidine or phenylalanine in resistant clinical isolates.
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Erg11 catalyzes 14-methylation of lanosterol in C. albicans through three cycles, each requiring two electrons from NADPH-dependent Ncp1.
“Erg11, a cytochrome P450 enzyme, catalyzes the 14-methylation of lanosterol in C. albicans through three cycles13,14, each requiring two electrons from nicotinamide adenine dinucleotide phosphate (NADPH)-dependent Ncp1 reductase15,16.”
From Impairing the interaction between Erg11 and cytochrome P450 reductase Ncp1 enhances azoles’ antifungal activities (2025) · cites this paper as [14]
The Introduction identifies Erg11p as a cytochrome P450 enzyme but says it catalyzes 14α-demethylation of lanosterol, the opposite of the claimed methylation. The paper studies S. cerevisiae Erg11p; the passages found do not establish three cycles or an Ncp1-dependent two-electron requirement in C. albicans. (LLM, conf=0.86)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredAzoles function by inhibiting Erg11 activity through binding to heme region of Erg11.
“Azoles function by inhibiting the activity of Erg11 through binding to the heme region of Erg1114, making them a preferred choice for primary treatment options due to their favorable bioavailability and safety profile56.”
From Impairing the interaction between Erg11 and cytochrome P450 reductase Ncp1 enhances azoles’ antifungal activities (2025) · cites this paper as [14]
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“Erg11,acytochromeP450enzyme,catalyzesthe14-methylationof lanosterol in C. albicans through three cycles 13,14 , each requiring two electrons from nicotinamide adenine dinucleotide phosphate (NADPH)-dependent Ncp1 reductase 15,16 .”
- Authors
- Sagatova, A. A., Keniya, M. V., Wilson, R. K., Monk, B. C., & Tyndall, J. D. A.
- Affiliations
- University of Otago (NZ)
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2015-08
- Volume
- 59
- Issue
- 8
- Pages
- 4982-4989
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC4505223
- OpenAlex
- W1954570499
- Cited by
- 210
- References
- 50
- Citations by year
- 2026: 21 · 2025: 28 · 2024: 33 · 2023: 19 · 2022: 14 · 2021: 22 · 2020: 13 · 2019: 20 · 2018: 15 · 2017: 14 · 2016: 10 · 2015: 1
- FWCI
- 10.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- fluconazole, lanosterol 14α-demethylase, Saccharomyces cerevisiae, CYP51, triazole resistance, ergosterol biosynthesis, cytochrome P450, hydrogen bond network, drug target structure, Candida albicans, Aspergillus fumigatus
- MeSH terms
- Antifungal Agents, Aspergillus fumigatus, Azoles, Candida albicans, Hydrogen Bonding, Lanosterol, Saccharomyces cerevisiae, Triazoles, Fluconazole, Crystallography, X-Ray, Drug Resistance, Multiple, Fungal, Sterol 14-Demethylase
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