Application of cryo-EM to understanding of signalling receptor structure, function and drug discovery

The potential of using for cryo-EM to explore the druggability of cell signalling receptors that play critical role in a number of human diseases will open new opportunities for drug discovery programs.  By targeting these challenging proteins, we will enable the development of small molecules and biologics that, with industry partners, will be translated to new generations of therapeutics. 

Receptor targets will be chosen based on alignment between potential industry partners and the host academic laboratories.

  

This work will be completed with the The Walter and Eliza Institute Node.

Project Areas

WEHI has a strong record in structure guided drug discovery. WEHI has recently established the National Drug Discovery Center with a mission to translate basic biological discoveries into tomorrow’s therapeutics and structural biology will play a key role in this newly established discovery pipeline. 

Structural basis of β-catenin-independent Wnt signalling: Glukhova Lab

The goal of this project is to understand the mechanism of ligand binding and activation of Frizzled receptors (FZD), class F GPCRs. The activation of FZD by Wnt proteins triggers a complex network of downstream signalling cascades. Wnt signalling is important in embryonic development and the maintenance of healthy tissue homeostasis in adults. Because of this, different members of Wnt signalling cascades are recognised as promising targets for the treatment of different human cancers.

In this project, we will use cryo-EM to determine the structure of the Wnt-FZD complex coupled to a heterotrimeric G protein, a known transducer in Wnt signalling pathways. We anticipate that this structural information will provide insights into the binding and selectivity for different FZD, Wnts, and G proteins. This project will also involve different biochemical and biophysical technics to get mechanistic insights into how this complex transmits the signal across the cell membrane.

 

Structural basis of Receptor Tyrosine Kinases signalling: Lucet Lab

The overarching goal of this project area will be to explore the therapeutic potential of subset of Receptor Tyrosine Kinases (RTK) with intracellular pseudokinase domains, called RTK-like. Membrane-bound RTK-like have recently emerged as critical regulators of Wnt signalling pathway that regulates epithelial mesenchymal transition (EMT) a process that controls planar cell polarity, cell-cell adhesion.  Deregulated expression and mutations of RTK-like enables the initiation of metastasis for cancer progression.

In this project area, we will focus on using cryo-EM to uncover the structure members of the RTK-like family known to have oncogenic properties. It is anticipated that cryo-EM atomic structures of membrane-bound RTK-like at high-resolution will provide the framework to identify new target-based approach to modulate Eph Receptor signalling. This project area will also capitalize on targeted genome editing technologies, advanced biochemistry and chemical biology and drug discovery approaches to fully elucidate the conformational dynamic and biological functions of RTK-like during development and cancer. This project is in close collaboration with our Industry Partner Catalyst Therapeutics

 

Structural basis for neuropilin-1 interaction with SARS-CoV-2: Shakeel Lab

Covid-19 caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is the current biggest global threat with 219 million cases and 4.55 million deaths so far. Vaccines are the most effective way to combat Covid-19 but they work only in prevention and not cure. An effective treatment to treat Covid-19 is still lacking. Some progress is made in developing monoclonal antibodies that block the interaction of spike protein of SARS-CoV-2 with the host cell surface receptor, angiotensin-converting enzyme 2 (ACE2). Besides ACE2 as the major receptor for SARS-CoV-2, two other cell surface molecules, neuropilin-1 and transmembrane protease serine 2 (TMPRSS2) have been implicated in enhanced infection of the virus. ACE2 is the major binding receptor and TMPRSS2 through its protease activity primes spike protein for infection, but the role of neuropilin-1 is still unclear except indications that it enhances virus entry.

In this project, we will structurally and biochemically characterise the interaction of neuroplin-1 bound to SARS-CoV-2 spike protein using advanced technology platforms such as protein expression systems, single-particle cryo-EM, biophysical and cellular assays. Such understanding at molecular level will aid in designing new therapeutic antibodies and small molecules targeting the Interaction of neuroplin-1 with SARS-CoV-2.