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Crystal structure and transient dimerization for the FKBP12 protein from the pathogenic fungus Candida auris
Qamar Bashir1, Zhong Li1, Hongmin Li1
1Wadsworth Center, New York State Department of Health, Empire State Plaza, Albany, NY, 12201, USA.
Abstract:
International concern over the recent emergence of Candida auris infections reflects not only its comparative ease of transmission and substantial mortality but the increasing level of resistance observed to all three major classes of antifungal drugs. Diminution in virulence has been reported for a wide range of fungal pathogens when the FK506-binding protein FKBP12 binds to that immunosuppressant drug and the binary complex then inhibits the fungal calcineurin signaling pathway. Structure-based drug design efforts have described modifications of FK506 which modestly reduce virulence for a number of fungal pathogens while also lessening the side effect of suppressing the tissue immunity response in the patient. To aid in such studies, we report the crystal structure of Candida auris FKBP12. As physiological relevance has been proposed for transient homodimerization interactions of distantly related fungal FKBP12 proteins, we report the solution NMR characterization of the homodimerization interactions of the FKBP12 proteins from both Candida auris and Candida glabrata.
Insights
Candida auris is a growing threat due to drug resistance. Researchers studied its FKBP12 protein structure and interactions to help design new antifungal drugs that reduce virulence and side effects.
Area of Science:
- Medical Mycology
- Structural Biology
- Drug Discovery
Background:
- Emergence of multidrug-resistant Candida auris infections poses a significant global health threat.
- The FK506-binding protein FKBP12 and calcineurin pathway are known virulence factors in fungal pathogens.
- Modifications to FK506 show potential for reducing fungal virulence and immunosuppression.
Purpose of the Study:
- To determine the crystal structure of Candida auris FKBP12.
- To characterize the homodimerization interactions of FKBP12 from Candida auris and Candida glabrata.
Main Methods:
- X-ray crystallography was used to determine the crystal structure of Candida auris FKBP12.
- Solution Nuclear Magnetic Resonance (NMR) spectroscopy was employed to study homodimerization interactions.
Main Results:
- The crystal structure of Candida auris FKBP12 was determined.
- Homodimerization interactions of FKBP12 from Candida auris and Candida glabrata were characterized in solution.
Conclusions:
- Structural and interaction data for Candida auris FKBP12 can aid structure-based drug design.
- Understanding FKBP12 interactions may lead to novel antifungal strategies targeting Candida species.
- This research contributes to developing new treatments for resistant fungal infections.
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