New microscopy technique to transform field of structural biology

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Electron microscope image

A new Industrial Transformation Training Centre for Cryo-electron Microscopy of Membrane Proteins (CCeMMP) has been established at the University of Melbourne’s Bio21 Molecular Science and Biotechnology Institute to train researchers in the use of cryo-electron microscopy (cryo-EM) for drug discovery.

Cryo-EM is a new technique that has transformed the field of structural biology by making it possible to determine the structure of membrane proteins without the need to crystallise them, as had previously been the case.

Associate Professor Isabelle Rouiller from the School of Biomedical Sciences explains that all the trillions of cells in an adult body which make up our tissues and organs are encased in a fatty ‘lipid’ membrane that acts as a barrier between the inside and outside of the cell or creates separate compartments within cells.

“The protein molecules embedded in these cell membranes are the key to how cells perceive their external and internal environment and communicate with each other. They function to instruct the cell how to behave, such as whether to divide, move, eat, or die. Immune cells can move to catch and eat or destroy infectious agents, such as the Covid-19 virus. When the cell isn’t receiving the correct messages because the membrane protein is no longer functioning properly, disease can occur.

“Membrane proteins are therefore important targets for developing new drugs to treat many diseases and health conditions. If you can stop the faulty communication by blocking the membrane protein, this can potentially treat or cure the disease. Or, alternatively, you can try to switch on a signal that has been silenced. Currently membrane proteins comprise 60 per cent of therapeutic drug targets for a range of different diseases such as cancer, heart disease and neurodegenerative diseases.”

It is through obtaining accurate images of the three-dimensional atomic structure of these membrane proteins, that scientists gain a wealth of information critical to the design, development and optimisation of new drugs and antibody treatments.

How Cryo-EM works

As the name implies, the 2017 Chemistry Nobel Prize-winning technique snap freezes samples of these membrane proteins so they can be observed while frozen (cryo) in their near ‘native’ or natural states, in the vacuum of instruments called electron microscopes.

These microscopes are incredibly powerful and yet very precise as they capture high-resolution images of sensitive biological samples. But the samples are extremely fragile and quickly destroyed by the electrons used during imagery. For this reason, the images collected by the cryo-electron microscopes are very fuzzy or ‘noisy’ and are like images taken under extremely low light conditions. So to retrieve useful information, researchers record thousands if not millions of noisy images of the proteins. From all these tens of thousands of ‘snapshots’ of different views of the protein, a computer-derived algorithm is able to calculate a three-dimensional, high-resolution ‘density map’ – or picture – of the protein. Researchers then build the atomic structure of the protein into the density map.

This structural information allows researchers to understand how the membrane protein is organised, how it functions, and how it interacts with various drugs. Determining the structure of the protein on its own, and when bound to these drugs, allows researchers to design new and better medicines more rapidly and cheaply than would otherwise be possible.

Pharmaceutical companies need industry researchers who can use these powerful new tools for drug design, and it’s therefore expected the centre will advance Australia’s biotechnological capability and build strong linkages between academia and industry.

About CCeMMP

CCeMMP is an initiative led by Monash University, together with principal partners the University of Melbourne, the University of Wollongong, and the Walter and Eliza Hall Institute.

Associate Professor Isabelle Rouiller from the Department of Biochemistry and Pharmacology in the School of Biomedical Sciences, is Deputy Director of the new ARC CCeMMP centre and heads the University of Melbourne node.

Professor Michael Parker (Bio21 Director, School of Biomedical Sciences, MDHS) and Associate Professor Michael Griffin (School of Biomedical Sciences, MDHS) are also project leaders/chief investigators within the Centre.

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