Galina Lepesheva
Vanderbilt University, TN·Biochemistry
Cytochrome P450 enzymes are one of the largest enzyme families on Earth. Some break down drugs and pollutants, while others act only on specific natural molecules such as steroids.
- Fields
Biochemistry
Biophysics
Pharmacology
- Topics
cytochrome P450
sterol 14α-demethylase
sterol biosynthesis
- Grants
- 1 known grant, through May 2029
What they work on
- Determine how large-scale shape changes guide CYP51, the sterol-making enzyme targeted by antifungal drugs, through each step of its three-step reaction, using X-ray crystallography, cryo-electron microscopy and computational approaches.
- Explain how CYP51 recognizes specific sterol substrates and responds to allosteric regulation by comparing enzymes from vertebrates, fungi, protozoa and, later, plants.
- Reveal how CYP51 assembles with its electron-donating partners, the cytochrome P450 reductases, and with membranes, using cryo-EM of the multi-protein electron transfer systems.
- Use a natural bacterial CYP51–ferredoxin fusion protein to probe the enzyme's bacterial origins and its possible role in the diversification of the P450 family.
More about the research
Sterol 14α-demethylase (CYP51) is a P450 found in all kingdoms of life and is thought to be the ancestor of all other P450s. It performs an essential step in making sterols, the cholesterol-like molecules that cell membranes need. CYP51 is the main drug target for treating fungal infections in people and plants. Understanding how its shape changes during the reaction could improve drug design and help explain how the P450 family diversified.
Why it matters
Knowing how CYP51 moves and pairs with its partner proteins could guide new drugs against fungal infections and protozoan parasites such as trypanosomes and leishmania. This knowledge could help address rising drug resistance in the clinic. The work may also establish the enzyme's partner-binding surface as a new site for inhibitors.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
James Solomon Fraser
University of California-San Francisco, CA·Biophysics
Improve computational methods for finding and modeling alternative protein shapes in cryoEM density maps, extending the multiconformer modeling the group built for X-ray crystallography.
Xiaojing Yang
University of Illinois Chicago, IL·Biophysics
Determine full-length cryo-EM structures of a bacteriophytochrome and a dual-sensor photoreceptor kinase in different signaling states by resolving structural heterogeneity, meaning the mix of shapes the proteins adopt.
Clara Kielkopf
University of Rochester, NY·Biochemistry
Compare how recurrent U2AF2 mutations found in neurodevelopmental disorders and in cancers affect RNA binding and splicing, using structural methods and pre-mRNA splicing assays in human cells.
The school
Vanderbilt University: 22 labs on PI Pages, $1.3B a year on research, 494 research doctorates a year.
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