Will Burn

In my research I use structural, biophysical and cell biology methods to study transmembrane receptor serine/threonine kinases. Regulation of signalling through these receptors is crucial for healthy growth and development. Even small changes to the activity of their pathways can drive the development of highly fatal brain cancers, cardiac diseases and 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-EM methods I am working to determine structures of RSTK complexes. This missing 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 to map the assembly mechanism of this family of kinases from inactive monomers to higher-order tetramers capable of binding intracellular signal transducers.

This structural work has also led to the determination of the first apo, transition, active and post-hydrolytic state structures of ACVR1 - a receptor kinase found to be mutated in Fibrodysplasia Ossificans Progressiva (FOP) and Diffuse Midline Glioma (DMG/DIPG) patients. Correlating this 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. To this end I am looking to find and develop small molecules to inhibit kinases. By crystallographic methods, I have solved novel structures of approved and investigational drugs bound to ACVR1/ALK2 to map their modes of binding and explain their varying affinities. Combining this information with biophysical data and cellular assays, we have shown how Pacritinib and Momelotinib, both FDA-approved kinase inhibitors, 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 this family of transmembrane RSTKs. 

I work as part of Professor Alex Bullock's group at The Centre for Medicines Discovery. My research is supported by the uk-based FOP Friends charity and The Oxford-Simcox Family Scholarship. 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.

Emails to ask about the research, teaching or possible collaborations are always welcome. 

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