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Structural
Biology

"For me, I love the discovery process. It's innate
within us; it's the same reason we took to the
ocean to explore our world, and then 
sent 12 others to step on the moon. Seeing the
machinery of life is a great privilege that
I’m very lucky to have, and getting to
tell these stories to the rest of the
world is a fantastic feeling,"

-Dr Alastair Stewart

Dr Alastair Stewart

Head, Structural Biology Laboratory

Research overview

Key Research Areas

  • Protein Structure 
  • Cyro Electron Microscopy 

Research Overview 

Dr Stewart’s research aims to understand one of the most fundamental unanswered questions of Biology: “How do we convert energy from nutrients into a biologically useful form?”  The most astonishing thing about this question is that inside every cell of our body we have thousands of microscopic generators.  These spin thousands of times a minute, generating all the energy we need to perform every step, thought and heartbeat of our lives.  Although we have known that these generators exist for many decades, we are still far from understanding how they actually work.

The Structural Biology Laboratory aims to establish the precise molecular architecture of these generators and in doing so, hopes to understand how these microscopic motors work.  Due to their small size, just a millionth of a centimetre across, his group is unable to use conventional light microscopes to see them.  Instead they use electrons to visualise these tiny machines at the molecular level.

research projects

There are 3 key projects underway in the Structural Biology Laboratory, led by Dr Alastair Stewart;

1. Mitochondrial disease

Mitochondrial disorders attributed to dysfunction of oxidative phosphorylation occur in approximately 1 in 5,000 live births. Organs with high-energy demands, such as brain, heart and skeletal muscle tissues are affected most severely and result in serious disorders, including intellectual disability, cardiomyopathies and heart failure. We aim to define the molecular basis of genetic disorders that affect the function of the proteins responsible for energy production in the cell.

2. Antimicrobial discovery

There is a pressing need for new antibiotics, with routine surgical procedures now often being complicated by subsequent multidrug-resistant bacterial infections. Virtually all known mechanisms of multidrug-resistance now being detected in Australia and the World Health Organisation recently prioritising basic science and advanced R&D directed towards new antibiotic discovery. We aim to use structural studies to guide novel antibiotic development towards proteins essential for biological energy production.

3. Stretch activated transcription regulation

ANKRD1 and 2 are proteins are cardiac specific proteins expressed in human cardiomyocytes, localised to the both the nuclei and Z-discs. Mutations in these proteins have been implicated in a wide range of conditions including dilated and hypertrophic cardiomyopathy. We aim to structurally and biochemically characterise these proteins, to gain a mechanistic understanding of disease-associated mutations.

laboratory members & collaborators

Laboratory

Meghna Sobti, Senior Research Officer 

James Walshe, Postdoctoral Scientist

Yi Zeng, Research Assistant

Collaborators 

Prof Carol Robinson, University of Oxford

Prof Richard Berry, University of Oxford

Assoc Prof Thomas Duncan, Upstate Medical University USA

Asst Prof Sara Sandin, NTU Singapore

publication highlights

  1. Sobti M, Walshe JL, Wu D, Ishmukhametov R, Zeng YC, Robinson CV, Berry RM, Stewart AG (May, 2020) 'Cryo-EM structures provide insight into how E. coli F1Fo ATP synthase accommodates symmetry mismatch' Nature Communications; doi.org/10.1038/s41467-020-16387-2
  2. Sobti M, Ishmukhametov R, Bouwer JC, Ayer A, Suarna C, Smith NJ, Christie M, Stocker R, Duncan TM, Stewart AG. (Mar, 2019), 'Cryo-EM reveals distinct conformations of E. coli ATP synthase on exposure to ATP', eLife doi.org/10.7554/eLife.4..
  3. Chorev DS, Baker LA, Wu D, Beilsten- Edmands V, Rouse SL, Zeev-Ben-Mordehai T, Jiko C, Samsudin F, Gerle C, Khalid S, Stewart AG, Matthews SJ, Grünewald K, Robinson CV, (Nov, 2018), 'Protein assemblies ejected directly from native membranes yield complexes for mass spectrometry', Science; doi.org/10.1126/science.aau0976
  4. Sobti M, Smits C, Wong ASW, Ishmukhametov R, Stock D, Sandin S, Stewart AG (Dec, 2016) 'Cryo-EM structures of the autoinhibited E. coli ATP synthase in three rotational states', eLife; doi.org/10.7554/eLife.21598
  5. Chaston JJ, Smits C, Aragao D, Ahsan B, Sandin S, Molugu SK, Molugu SK, Bernal RA, Stock D Stewart AG. (Mar 2016), 'Structural and functional insights into the evolution and stress adaptation of type II chaperonins', Structure; doi.org/10.1016/j.str.2015.12.016
  6. Zhou M, Politis A, Davies R, Liko I, Wu KJ, Stewart AG, Stock D, Robinson CV. (Feb, 2014), 'Ion mobility mass spectrometry of a rotary ATPase reveals ATP induced reduction in conformational flexibility', Nature Chemistry ; doi.org/10.1038/nchem.1868
  7. Stewart AG, Sobti M, Laming E, Stock D, (Apr, 2014), 'Rotary ATPases - dynamic molecular machines', Current Opinion in Structural Biology ; doi.org/10.1016/j.sbi.2013.11.013
  8. Stewart AG, Lee LK, Donohoe M, Chaston JJ, Stock D (Feb, 2012), 'The dynamic stator stalk of rotary ATPases', Nature Communications; doi.org/10.1038/ncomms1693
  9. Lee LK, Stewart AG, Donohoe M, Bernal RA, Stock D. (Feb, 2010), 'The structure of the peripheral stalk of T. thermophilus H+-ATPase/synthase', Nature Structural & Molecular Biology; http://doi.org/10.1038/nsmb.1761