Will Burn

In my research I use complementary structural, biophysical and cell biology methods to study transmembrane receptor serine/threonine kinases. Signalling through these receptors is important for healthy growth and development. Changes to this signalling have been found to contribute to the development of highly fatal brain cancers, cardiac diseases and rare bone disorders. I'm interested in understanding the molecular mechanisms underlying these changes and doing what I can to speed up the discovery of medicine.

Using crystallography and cryo-electron microscopy methods I am working to determine structures of receptor ser/thr kinase complexes. This structural information has the potential to shed light on how healthy and pathogenic signalling is activated in the human body and how it may be controlled with medicine. These structures are difficult to solve due to their small size, transience, low affinity interactions and heterogeneous phosphorylation patterns. Despite these challenges, advances in structural methods now make it possible for these assemblies to be visualised in high-resolution detail. Because of these developments we have for the first time been able to resolve complexes of type-1 and type-2 BMP receptor kinases and their intracellular substrates. These structures have helped map the assembly mechanism of this family of kinases from inactive monomers to higher-order oligomers capable of binding signal transducers. This structural work has also led to the determination of the first apo, transition, active and post-hydrolytic state structures of ACVR1.

Correlating our structural and biophysical data with cell-based functional studies continues to provide insight into how a range of mutations identified in patients contribute to disease severity and progression. I'm interested in extending this work to include other kinases from the superfamily of TGF-β receptors and developing techniques to isolate native receptor assemblies from human cells for visualisation by cryo-EM.

The ultimate purpose of my research is to speed up the discovery of medicines to treat disorders caused by deregulated kinase signalling. Beyond understanding the structural mechanisms underlying the biology, I have an interest in finding and developing small molecules to inhibit kinases. We have solved novel structures of approved and investigational drugs bound to ACVR1, the kinase found to be mutated in Fibrodysplasia Ossificans Progressiva (FOP) patients and contributing to the development of highly-fatal Diffuse Midline Gliomas (DMG/DIPG). Combining this structural information with biophysical data and cellular assays, we have shown how Pacritinib, an FDA-approved JAK inhibitor, may be of therapeutic use in treating FOP. In collaboration with other groups we are also in the process of developing first-in-class covalent and allosteric inhibitors against ACVR1.

I work as part of Professor Alex Bullock's group at The Centre for Medicines Discovery. I was previously a member of Professor Peijun Zhang's lab in The Division of Structural Biology where I used cryo-ET STA to study the protein:protein interactions essential for the self-assembly of bacterial microcompartments. 

https://www.nature.com/articles/s41467-022-32004-w