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Flavin-Dependent Thymidylate Synthase as a Drug Target for Deadly Microbes: Mutational Study and a Strategy for
1Stanford Synchrotron Radiation Lightsource, Stanford University, Menlo Park, CA 94025, USA.
Flavin-dependent thymidylate synthase (FDTS) is a key target for new antimicrobials. Structural differences between microbial FDTS and human enzymes enable the design of pathogen-specific drugs.
Area of Science:
- Biochemistry
- Structural Biology
- Drug Discovery
Background:
- Flavin-dependent thymidylate synthase (FDTS) is essential in pathogenic microbes.
- FDTS differs from human thymidylate synthase in cofactor usage (FAD and NAD(P)H).
- These differences offer a basis for selective antimicrobial drug development.
Purpose of the Study:
- To determine the crystal structure of FDTS in complex with methyl donor CH2H4 folate.
- To compare FDTS mutant structures with existing complex structures.
- To identify structural features for designing FDTS-specific inhibitors.
Main Methods:
- X-ray crystallography
- Structure determination of FDTS-CH2H4 folate complex
- Comparative structural analysis
Main Results:
- Determined the crystal structure of FDTS complexed with CH2H4 folate.
- Identified a crucial conformational change linked to substrate binding.
- Compared structures to reveal differences and similarities.
Conclusions:
- FDTS is a viable drug target for antimicrobial development.
- Structural insights facilitate the design of novel FDTS inhibitors.
- Understanding conformational changes aids in developing pathogen-specific therapeutics.
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