James Murphy - Projects

James Murphy - Projects


Super Content: 
Dr James Murphy and Dr Isabelle Lucet in the lab

Dr James Murphy and Dr Isabelle Lucet have created a 3D image of a key cancer protein, a finding which could be used to develop new cancer treatments.

How does the “dead” enzyme MLKL induce cell death?

The pseudokinase, MLKL, is the terminal effector in the necroptosis cell death pathway. Our structural studies and development of MLKL-deficient laboratory models have enabled us to greatly advance mechanistic knowledge of this protein. Our ongoing work is directed toward understanding how MLKL kills cells following its activation by the upstream protein kinase, RIPK3, and the role of this pathway in causing inflammatory diseases and cancer. These studies are highly collaborative and draw upon in vivo biology, structural biology, molecular and cellular biology, biochemistry, chemical biology and proteomics approaches.

Small molecules to explore the biology of MLKL

Pseudokinases such as MLKL have only recently become seriously considered as therapeutic targets. We recently reported the discovery of a proof-of-concept small molecule, Compound 1 (discovered in collaboration with Dr Isabelle Lucet), which inhibits necroptosis in cells. This compound forms the basis for the development of tool compounds for studying the cell biology and biochemistry of MLKL-driven necroptosis (with Associate Professor Guillaume Lessene).

The emerging roles of pseudokinases in disease

We recently characterised the nucleotide binding properties of 31 diverse pseudokinase domains, and have assembled a pseudokinase library that encompasses half of the human pseudokinome (in collaboration with Dr Isabelle Lucet). Ongoing work seeks to define the biological functions of these proteins and establish their candidacy as drug targets to counter human diseases, especially inflammatory and proliferative diseases. 

Structure-function characterisation of the epigenetic regulator, Smchd1

Smchd1 is a poorly understood protein comprising an N-terminal ATPase and C-terminal hinge domain. Our recent studies have sought to understand the biological functions (in collaboration with Dr Marnie Blewitt) and structures (in collaboration with Dr Peter Czabotar) of the component domains with a view to understanding its pleiotropic roles as a tumour suppressor, in X chromosome inactivation and gene imprinting.