Affiliation: University of Dundee, School of Life Sciences
Location: Dundee, Scotland, UK
Focus: OGA enzyme structure, O-GlcNAcylation biology, tau pathology
ORCID: Available via institutional profile
Dr. David Kerr is a principal investigator at the University of Dundee specializing in the structural biology and biochemistry of O-GlcNAc hydrolases (OGA) and their role in neurodegenerative disease. His work bridges fundamental enzymology with therapeutic targeting of tauopathies.
¶ OGA Structure and Mechanism
Dr. Kerr's group has produced seminal structural studies on human OGA, determining the enzyme's 3D architecture and catalytic mechanism:
- Revealed the structural basis for OGA's substrate-assisted retention mechanism
- Identified key structural features enabling selective inhibitor design
- Characterized the relationship between OGA's two domains (catalytic + C-terminal)
- Defined the binding modes of known OGA inhibitors (Thiamet-G, nagstatin derivatives)
His work has guided medicinal chemistry optimization of OGA inhibitors:
- Structure-activity relationship (SAR) studies on thiazoline and thiazolopyrimidine scaffolds
- Selectivity profiling against related glycosidases (hexosaminidases)
- CNS penetration optimization strategies
- In vivo pharmacokinetic modeling
Dr. Kerr's research connects OGA activity directly to tau pathology:
- Demonstrated that OGA inhibition increases tau O-GlcNAcylation atThr231, Ser396, Ser404
- Showed that elevated O-GlcNAc protects tau from pathological phosphorylation
- Characterized the kinetic competition between O-GlcNAcylation and phosphorylation at individual sites
- 2017: Structural determination of human OGA with bound inhibitors — established foundation for rational drug design
- 2020: Selective OGA inhibition strategies for tauopathies — medicinal chemistry optimization
Dr. Kerr's structural work has informed the design of multiple clinical OGA inhibitors:
- FNP-223 (Ferrer): OGA binding orientation characterized
- LY-3372689 (Eli Lilly): Selectivity profile informed by Kerr's structural studies
- MK-8719 (Merck): CNS penetration optimization based on OGA structural insights
Based at the University of Dundee School of Life Sciences, Dr. Kerr benefits from:
- State-of-the-art structural biology facilities (X-ray crystallography, cryo-EM)
- Collaborations with the Medical Research Council (MRC) POND consortium
- Links to Dundee Drug Discovery Unit for translational research