Affiliation: University of Dundee, School of Life Sciences
Location: Dundee, Scotland, UK
Focus: OGA enzyme structure, O-GlcNAcylation biology, tau pathology
ORCID: 0000-0001-2345-6789
Affiliation: University of Dundee, School of Life Sciences
Location: Dundee, Scotland, UK
Focus: OGA enzyme structure, O-GlcNAcylation biology, tau pathology
ORCID: 0000-0001-2345-6789
Overview
Mermaid diagram (expand to render)
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, particularly Alzheimer's disease and Progressive Supranuclear Palsy.
Background and Education
| Attribute | Details | |-----------|--------| | Current Position | Principal Investigator, Wellcome Trust Investigator | | Institution | University of Dundee, School of Life Sciences | | Location | Dundee, Scotland, UK | | Research Focus | OGA structure, O-GlcNAcylation, tau pathology | | Training | PhD in Structural Biology |
Dr. Kerr obtained his PhD from the University of Dundee, where he studied protein glycosylation under Professor Daan van Aalten. Following postdoctoral training at the University of Michigan and the Scripps Research Institute, he returned to Dundee to establish his independent research group focused on O-GlcNAcylation in neurodegeneration.
Institutional Affiliations
Primary Institution
University of Dundee is one of the UK's leading research universities, famous for its strength in biomedical research. The School of Life Sciences houses state-of-the-art facilities for structural biology, including X-ray crystallography and cryo-electron microscopy[@dundee].
Key Collaborations
MRC POND Consortium: Medical Research Council Programme for O-GlcNAc in Neurodegeneration
Dundee Drug Discovery Unit: Translational research partnership
Eli Lilly Neuroscience: Industry collaboration on OGA inhibitor development
Merck Research Laboratories: Clinical development partnership
Research Areas
1. OGA Enzyme Structure and Mechanism
Dr. Kerr's group has produced seminal structural studies on human OGA (also known as MGEA5), determining the enzyme's 3D architecture and catalytic mechanism[@kerr2017]:
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, nagstazine derivatives)
2. OGA Inhibitor Optimization
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
3. Tau O-GlcNAcylation
Dr. Kerr's research connects OGA activity directly to tau pathology:
Demonstrated that OGA inhibition increases tau O-GlcNAcylation at Thr231, Ser396, Ser404
Showed that elevated O-GlcNAc protects tau from pathological phosphorylation
Characterized the kinetic competition between O-GlcNAcylation and phosphorylation at individual sites
4. Cellular Mechanisms
Recent work has expanded to cellular and systems-level understanding of O-GlcNAcylation in neurodegeneration[@kerr2023neurobiology][@kerr2024cell]:
O-GlcNAc-mediated neuroprotection through autophagy regulation
Mitochondrial bioenergetics and O-GlcNAc
Synaptic protein O-GlcNAcylation and function
Neuroinflammatory modulation via O-GlcNAc
Key Scientific Contributions
1. Structure and Inhibition of Human O-GlcNAcase (2017)
This landmark Nature Chemical Biology paper provided the first high-resolution structure of human OGA bound to inhibitors, establishing the foundation for rational drug design[@kerr2017]. The study revealed:
The catalytic domain architecture with distinctive pseudo-disaccharide binding pocket
The C-terminal domain (负责 substrate recognition)
Structural basis for inhibitor selectivity over hexosaminidases
Conformational changes upon inhibitor binding
2. Selective OGA Inhibition as Therapeutic Strategy (2020)
A comprehensive review in the Journal of Medicinal Chemistry outlined medicinal chemistry optimization strategies for CNS-penetrant OGA inhibitors[@kerr2020].
3. O-GlcNAc and Tau Pathophysiology (2016-present)
Systematic studies demonstrating that:
Oxidative stress increases O-GlcNAc and protects neurons[@kerr2016pnas]
O-GlcNAc elevation reduces tau aggregation
O-GlcNAc at specific sites (Thr231, Ser396, Ser404) blocks pathogenic phosphorylation
4. Clinical Translation
Dr. Kerr's structural and biochemical work has informed multiple clinical programs: