Structural
Biology

"For me its the discovery. Its innate within us;
its the same reason we took to the
ocean and explored our world, and the
sent 12 others to step on another. 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

Jessica Chaston, Postdoctoral Scientist 

Meghna Sobti, Senior Research Officer 

Collaborators 

Asst Prof Sara Sandin, NTU,

Dr Robert Ishmukhametov, University of Oxford

publication highlights

1. Roberta B. Davies, Callum Smits, Andrew S.W. Wong, Daniela Stock, Mary Christie, Sara Sandin and Alastair G. Stewart+ (2017). “Cryo-EM analysis of a domain antibody bound rotary ATPase complex.” Journal of Structural Biology (doi: 10.1016/j.jsb.2017.01.002).

2. Meghna Sobti, Callum Smits, Andrew S.W. Wong, Robert Ishmukhametov, Daniela Stock, Sara Sandin and Alastair G. Stewart+ (2016). “Cryo-EM structures of the autoinhibited E. coli ATP synthase in three rotational states.” eLife (doi: 10.7554/eLife.21598).

3. Tony Ngo, Andrey V. Ilatovskiy, Alastair G. Stewart, James L.J. Coleman, Fiona M. McRobb, R. Peter Riek, Robert M. Graham, Ruben Abagyan, Irina Kufareva, Nicola J. Smith. (2016). “GPCR-CoINPocket: pickpocketing pharmacological neighbors reveals ligands for orphan receptors.” Nature Chemical Biology  (doi: 10.1038/nchembio.2266).

4. Walid A Al-Zyoud, Robert MG Hynson, Adelle CF Coster, Lorraine Ganuelas, Anthony P Duff, Matthew Baker, Alastair G Stewart, Katharina Gaus, Dali Liu, Lawrence K Lee & Till Böcking. (2016). “Binding of transcription factor GabR to DNA requires recognition of DNA shape at a location distinct from its cognate binding site”. Nucleic Acids Research 44(3):1411-20 (doi: 10.1093/nar/gkv1466).

5. Mary Christie, Chiung-Wen Chang, Gergely Róna, Kate M Smith, Alastair G Stewart, Agnes A S Takeda, Marcos R M Fontes, Murray Stewart, Beáta G Vértessy, Jade K Forwood & Bostjan Kobe. (2016). “Structural biology and regulation of protein import into the nucleus.” Journal of Molecular Biology 22:428 (doi:10.1016/j.jmb.2015.10.023). 

6. Jessica J Chaston, Callum Smits, David Aragao, Bilal Ahsan, Sara Sandin, Sudheer K Molugu, Sanjay K Molugu, Ricardo A Bernal, Daniela Stock+ & Alastair G Stewart+. (2016). “Structural and functional insights into the evolution and stress adaptation of type II chaperonins.” Structure 24:364-374 (doi: 10.1016/j.str.2015.12.016).

7. Min Zhou , Argyris Politis, Roberta Davies, Idlir Liko, Kuan-Jung Wu, Alastair G Stewart, Daniela Stock & Carol V Robinson. (2014). “Ion mobility mass spectrometry of a rotary ATPase reveals ATP induced reduction in conformational flexibility.” Nature Chemistry 6:208-215 (doi: 10.1038/nchem.1868). 

8. Alastair G Stewart+, Meghna Sobti, Elise Laming & Daniela Stock. (2014). “Rotary ATPases - dynamic molecular machines.” Current Opinion in Structural Biology 25:40-48 (doi: 10.1016/j.sbi.2013.11.013). 

9. Alastair G Stewart+ (2014). “The Molecular V Brake.” Journal of Molecular Biology 426:274-274 (doi: 10.1016/j.jmb.2013.10.003). 

10. Alastair G Stewart, Meghna Sobti, Richard P Harvey & Daniela Stock. (2013). “Rotary ATPases: Models, machine elements and technical specifications.” BioArchitecture 3:2-12 (doi: 10.4161/bioa.23301).

11. Alastair G Stewart+ & Daniela Stock+. (2012). “Priming a molecular motor for disassembly.” Structure 20:1799-1800 (doi: 10.1016/j.str.2012.10.003). 

12. Alastair G Stewart, Lawrence K Lee, Mhairi Donohoe, Jessica J Chaston & Daniela Stock. (2012). “The dynamic stator stalk of rotary ATPases.” Nature Communications 3:687 (doi: 10.1038/ncomms1693). 

13. Lawrence K Lee*, Alastair G Stewart*, Mhairi Donohoe, Ricardo A Bernal & Daniela Stock. (2010). “The structure of the peripheral stalk of T. thermophilus H+-ATPase/synthase.” Nature Structural & Molecular Biology 17:373-378 (doi: 10.1038/nsmb.1761). 

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