Molecular Machines in Health and Human Disease

Our research is motivated by the fundamental need to understand how proteins come together and function as large and intricately-assembled macromolecular machines.

 

The arrival of the 'genomic era' at the start of the 21st century brought with it unprecedented capabilities to identify the genes and proteins that are linked to human diseases. But in the current post-genomic era, it has becoming increasingly clear that a list of genes involved in disesase is not sufficient. 

Genes and the proteins they encode rarely act in isolation; rather they form networks of interactions with proteins and other molecules. Obtaining a full appreciation of how proteins come together and interact - resulting in specific functional consequences - is thus critical in order to properly understand the biological consequences associated with genetic mutations and dysfunctional proteins.

 

Our research is focused on understanding the specific roles played by large, multi-protein (or multi-molecular) structures that are assembled either temporarily or more permanently from many smaller subunits to cooperatively achieve a specific cellular function (or functions).  We have a particular interest in understanding fundamental mechanisms that enable infection by viruses and pathogenic bacteria, something we seek to achieve by obtaining a clearer picture of the molecular structures that are involved in these mechanisms.

 

Our group was the first to elucidate the structure of a family of bacterial proteins which assemble into remarkably unique, intercellular molecular transportation devices. Prior to this, we were also one of several groups to concurrently obtain the first detailed insights into the assembly of a key controlling enzyme, hijacked during infection by viruses such as HIV and Ebola and also utilised by cells to facilitate division and protein recycling. In the course of our research, we also develop new technical methods, some of which have been adopted by wider scientific communities.

 

Our technical focus is on the determination of protein structures, principally using cryo-electron microscopy (cryo-EM), in order to understand function and provide a platform for interrogating detailed aspects of molecular mechanism. Historically thought of as bridging the "resolution gap" between light microscopy (which can visualise small cells and large organelles) and methods for indirectly visualising protein structures, such as X-ray diffraction and Nuclear Magnetic Resonance spectroscopy, recent exciting developments in cryo-EM imaging have placed us in a position where we can now directly visualise large macromolecular machines (and even smaller assemblies) at levels of detail that rival the capabilities of those historically preferred methods for protein structure determination.  This opens up the unprecedented opportunity to directly image biological molecules on a scale that allows their structures to be understood at a near atomic level, paving the way for an exciting new era in structural and molecular biology research.

QUICK LINKS

Recent Structures [more here]

EMD-8625

MAL TIR-domain filament

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Lab News [more here]

Our latest paper was published overnight in Nature Structural and Molecular Biology. The work is the result of a productive collaboration with our neighbours in the Kobe Lab and Ed Egelman at the University of Virginia and describes the structure of a filamentous assembly formed by proteins involved in immune signalling through the cell surface receptor TLR4. A link to the paper is available on our publications page.

1 Aug, 2017

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