McDonald lab

Signalling and Structural Biology Laboratory

: Areas of interest

This figure shows the scales that we work with in the lab

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Our primary interests are the structural biology of neurotrophic factor receptor signalling in cancer, activation of rho-dependent protein kinases and drug resistance mechanisms.

We use structural biology to study the components and molecular assemblies involved in neurotrophic factor receptor signalling. Neurotrophic factor receptors are altered in both endocrine and lung cancers driving tumour growth. Understanding the mechanisms underpinning neurotrophic factor receptor signalling and how they are subverted in an oncogenic setting is crucial for new approaches to disease management.

Our laboratory works on the structural biology of neurotrophic factor receptor signalling. These receptors are trafficked to neuronal synapses where ligand engagement stimulates trophic support of both developing and mature neurons. In some contexts, the same ligands trigger cell adhesion. We are also interested in pathways activated by these receptors including those involving activation of Rho-family GTPases and their downstream effector kinases and partners. Neurotrophic factor receptors are targeted for oncogenic mutation and oncogenic fusion in both endocrine and lung cancers. We are interested in how both mutations and fusions deregulate these receptors as well as defining their physiological activation mechanisms.

We use structural biology as our primary tool and with recent technological advances in X-ray free electron lasers and cryo-electron microscopy, the size and complexity of targets that can be studied has dramatically improved. Structures of our biomedically important targets provide insights into molecular function, specificity and disease roles but also provide a platform for structure-based drug-design in an academic setting or with industrial collaborations. The laboratory has ongoing interests in developing modulators of both serine/threonine and tyrosine-directed kinases as well as the XPF-family endonucleases to tackle to cancer drug resistance.