Dr Christopher John Squire
Research | Current
NEW: We are currently recruiting students for 2017 and 2018 for our Protein "superglue" biotechnology themed projects. Have a read below and on the findathesis website for more details and please email me if you are interested!
My research focus is on understanding complex biological questions using the methods of structural biology. Selected research themes are described briefly below but focus on cancer biology and drug discovery although we cover a mix of eclectic projects! We work closely in multidisciplinary teams to advance our research aims with collaborators from fields including cancer signalling and cell biology, medicinal chemistry, computational biology and molecular modelling, evolutionary biology, immunology, and clinical science.
For some news about our latest project "molecular superglue" see the link below:
1. Protein "superglue" to build enzyme factories, bio-batteries, and biosensors
Current battery technology uses non-renewable materials that are toxic and environmentally hazardous. Green technology, incorporating enzymatic pathways inside bio-batteries avoids toxic materials and uses renewable chemicals as fueks (e.g. sugar solutions).
We are harnessing features of bacterial surface proteins to make so called "molecular superglue" to build complex nanostructures including green tech biological batteries, biosensors for measuring low level metabolites in diseases, and also enzymatic factories to produce rare or expensive natural products as drugs.
2. Targeting the PI3Kγ signalosome for cancer
Our focus in this project is on understanding the function and druggability of a signalling complex or signalosome central to inflammation and cancer progression. This signalling complex is built around the phosphoinositide 3-kinase gamma (PI3Kγ) protein that is coupled to activated G-protein coupled receptors (GPCRs). This pathway has been identified as having oncogenic effect via aberrant signalling, through promoting tumour inflammation, and has a role in cancer cell proliferation, migration, invasion, and adherence. So PI3Kγ signalling in both the cancer and its supporting microenvironment contributes to tumour development and blocking it has potentially therapeutic effects.
But how exactly does PI3Kγ physically couple to activated GPCRs? This remains one the great mysteries at the interface of two heavily studied and highly clinically relevant cell signalling systems. The accompanying figure shows a basic signalling scheme for connecting GPCRs to PI3K signalling highlighting the PI3Kγ catalytic (p110) and regulatory (p101) halves. In particular, neither the domain organisation nor structure of the fundamental regulatory p101 component is known; this is our focus.
Our goal is to characterise the regulation of PI3Kγ signalling in cancer, investigate the effects of somatic mutations, and discover novel inhibitors of this system. For more information about our collaborators at the Medical School please see their staff profiles:
3. Targeting protein kinases for cancer drug discovery
Fibroblast growth factor receptor 1 (FGFR1) and epidermal growth factor receptor (EGFR) are receptor tyrosine kinases and validated cancer drugs targets. Our aim is to discover or build new inhibitors of these proteins to target cancer and to have real impact on the lives of cancer patients. We work in collaboration with cancer biologists, computational biologists, chemists, and oncology clinicians at the world-renowned Auckland Cancer Society Research Centre (ACSRC) to progress our aims using a multidisciplinary approach. We provide structural information to shortcut the drug discovery process and use X-ray crystallography and state-of-the-art techniques like fragment screening. We have recently produced 12 crystal structures of FGFR kinase with potent inhibitors clearly visualised in the active site – we have the ingredients for truly rational drug design and discovery!
For more information about our ACSRC collaborators please see the ACSRC websitehttps://www.fmhs.auckland.ac.nz/en/sms/about/our-departments/auckland-cancer-society-research-centre.html and check out our collaborators profiles [Adam Patterson, Jeff Smaill, Jack Flanagan, and Mark McKeage]
4. Enzymatic prodrug activation – a powerful paradigm in cancer drug discovery
Medical researchers in the Auckland Cancer Society Research Centre (ACRSC) have discovered a novel activation mechanism for a series of anticancer prodrugs (one of which has reached stage II clinical trials) involving enzymatic nitroreduction.
Prodrugs are inactive forms of potentially toxic or unstable drug compounds that are activated selectively at tumour sites. We aim to characterize the structural basis of the enzymatic activation of a family of DNA-targeting nitrogen mustards via X-ray crystallography, thermal stability analysis, UV fluorescence, and mutational and functional assays of the protein. Currently, we have one protein crystal structure containing a prototype mustard, the compound currently in stage II trials, with the aim of investigating others in the series. We aim to provide feedback to the chemists in the ACSRC so they can develop more selective and more powerful anticancer prodrugs. A project with ACSRC researchers Adam Patterson and Jeff Smaill.
5. Fragment screening for drug discovery
Fragment screening is a widely-used, contemporary method used in drug discovery. Hundreds of small fragments of drug-like molecules are mixed with target protein and their binding assessed by thermal stability assays, NMR, molecular modelling, and X-ray crystallography. Fragments can then be “grown” to fit better the protein active site or two fragments can be linked chemically to make a larger drug-like molecule. Currently, we have drug targets from M. tuberculosis, human cancer targets, and immunology targets. These projects involve many other research groups from the School of Biological Sciences, Auckland Cancer Society Research Centre, and the Chemistry Department, with expertise in immunology, cancer biology, synthetic chemistry, and molecular modelling.
Areas of expertise
Selected publications and creative works (Research Outputs)
- Soo, V. W. C., Yosaatmadja, Y., Squire, C. J., & Patrick, W. M. (2016). Mechanistic and Evolutionary Insights from the Reciprocal Promiscuity of Two Pyridoxal Phosphate-dependent Enzymes. The Journal of biological chemistry, 291 (38), 19873-19887. 10.1074/jbc.m116.739557
Other University of Auckland co-authors: Yuliana Yosaatmadja
- Yeung, H., Squire, C. J., Yosaatmadja, Y., Panjikar, S., López G, Molina, A., ... Brimble, M. A. (2016). Radiation Damage and Racemic Protein Crystallography Reveal the Unique Structure of the GASA/Snakin Protein Superfamily. Angewandte Chemie (International ed. in English), 55 (28), 7930-7933. 10.1002/anie.201602719
Other University of Auckland co-authors: Edward Baker, Margaret Brimble, Paul Harris, Yuliana Yosaatmadja
- Young, P. G., Kwon, H., Baker, E. N., & Squire, C. J. (2016). Engineering protein stability with an intra-molecular isopeptide bond. Paper presented at Synthetic Biology Cutting Edge Symposium, Canberra, Australia. 4 April - 5 April 2016. Related URL.
Other University of Auckland co-authors: Paul Young, Edward Baker
- Bashiri, G., Rehan, A. M., Sreebhavan, S., Baker, H. M., Baker, E. N., & Squire, C. J. (2016). Elongation of the Poly-γ-glutamate Tail of F420 Requires Both Domains of the F420:γ-Glutamyl Ligase (FbiB) of Mycobacterium tuberculosis. Journal of Biological Chemistry, 291 (13), 6882-6894. 10.1074/jbc.M115.689026
Other University of Auckland co-authors: Ghader Bashiri, Edward Baker
- Yosaatmadja, Y., Silva, S., Dickson, J. M., Patterson, A. V., Smaill, J. B., Flanagan, J. U., ... Squire, C. J. (2015). Binding mode of the breakthrough inhibitor AZD9291 to epidermal growth factor receptor revealed. Journal of Structural Biology, 192 (3), 539-544. 10.1016/j.jsb.2015.10.018
Other University of Auckland co-authors: James Dickson, Adam Patterson, Jeffrey Smaill, Jack Flanagan, Yuliana Yosaatmadja, Mark McKeage
- Baker, E. N., Squire, C. J., & Young, P. G. (2015). Self-generated covalent cross-links in the cell-surface adhesins of Gram-positive bacteria. Biochem Soc Trans, 43 (5), 787-794. 10.1042/BST20150066
Other University of Auckland co-authors: Paul Young, Edward Baker
- Yosaatmadja, Y., Patterson, A. V., Smaill, J. B., & Squire, C. J. (2015). The 1.65 Å resolution structure of the complex of AZD4547 with the kinase domain of FGFR1 displays exquisite molecular recognition. Acta Crystallographica Section D: Biological Crystallography, 71 (Part 3), 525-533. 10.1107/S1399004714027539
Other University of Auckland co-authors: Adam Patterson, Jeffrey Smaill, Yuliana Yosaatmadja
- Herbert, M. H., Squire, C. J., & Mercer, A. A. (2015). Poxviral Ankyrin Proteins. Viruses, 7 (2), 709-738. 10.3390/v7020709