Synthetic protein adaptors to enable cryo-EM reconstruction of small druggable proteins

• PhD

Protein structures help us design effective vaccines, improve the potency and selectivity of drugs, and understand how mutations result in dysfunction and disease. While cryo-electron microscopy (cryo-EM) is the leading structural biology method to determine protein structures, many druggable and disease-associated proteins are too small to reconstruct by cryo-EM. While it is possible to use biological adaptor proteins such as antibodies to bind to and increase the size of protein targets, synthetic protein design enables the creation of custom adaptors. This method utilises deep-learning models to diffuse protein structures from noise and AI-driven protein structure prediction to screen binders in silico (Watson, Nature 2023 620:1089-1100). This project will design synthetic binders to aid structure-guided drug discovery for kinases important in cancer.

This project is eligible for the WEHI Artificial Intelligence (AI) & Machine Learning (ML) PhD Scholarship and is open to both domestic and international students.

The Lucet laboratory studies protein kinases, an evolutionarily conserved family of proteins that play a significant role in regulating every aspect of the cell function, including growth, differentiation and cell death. Protein kinases, through their catalytic activity, transfer a phosphate from ATP to a target protein, thus modifying the function of other proteins in the cell. Hence, mutations in protein kinases or their abnormal levels are the underlying cause of many human diseases, including developmental disorders and cancer, making them targets for therapy.

We employ a multidisciplinary approach including kinase biochemistry and biology, structural biology (X-ray crystallography and cryo-electron microscopy), assay development, high-throughput screening, proteomics, imaging and chemical biology to gain high-resolution insights into kinase/pseudokinase signalling proteins.