Associate Professor Christopher John Squire
PhD, University of Auckland
Research | Current
My research interests are wide and varied - please have a look below and on the findathesis site for potential student projects. Email me if you are interested!
My research focus is on understanding complex biological questions primarily using the methods of structural biology. Selected research themes are described briefly below but focus on cancer biology, drug discovery, and bacterial surface proteins, 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.
1. Targeting protein kinases for cancer drug discovery
(a) 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!
(b) Phosphoinositide 3-kinase (PI3K) signalling pathways can promote tumourigenesis and inflammation. The PI3Kγ isoform in particular has a role in cancer cell proliferation, migration, invasion, and adherence, and relies on coupling to activated GPCRs.
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. New methods being developed in my laboratory (see 3. below) will be applied to PI3Kγ and GPCR to visualise their structures at the membrane surface.
For more information see:
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
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
Check out the ACSRC and our collaborators:
2. Protein "superglue" to build enzyme factories and other nanoassemblys
We have extensively studied unique protein domains in bacterial surface proteins called adhesins that allow bacteria to stick to each other, form biofilms, and stick to host cells. These adhesins are very narrow structures but also extremely strong - they are held together by intramolecular cross-links often called "molecular superglue".
We are harnessing these molecular superglues to join together proteins and build complex nanostructures including enzymatic factories to produce rare or expensive natural products as clinical drugs.
For more information see:
Young, P. G., Yosaatmadja, Y., Harris, P. W. R., Leung, I. K. H., Baker, E. N., & Squire, C. J. (2017). Harnessing ester bond chemistry for protein ligation. Chemical Communications, 53 (9), 1502-1505. 10.1039/c6cc09899a
Kwon, H., Squire, C. J., Young, P. G., & Baker, E. N. (2014). Autocatalytically generated Thr-Gln ester bond cross-links stabilize the repetitive Ig-domain shaft of a bacterial cell surface adhesin. Proceedings of the National Academy of Sciences of USA, 111 (4), 1367-1372. 10.1073/pnas.1316855111
3. Novel methods for membrane protein visualisation - NEW PROJECT
Visualising small membrane proteins is fraught with difficulty and heartache! We have recently developed some novel ideas about how we might make accessible electromicroscopy visualisation of even the smallest of membrane proteins in a native-like evironment.
Areas of expertise
Selected publications and creative works (Research Outputs)
- Lin, X., Yosaatmadja, Y., Kalyukina, M., Middleditch, M. J., Zhang, Z., Lu, X., ... Squire, C. J. (2019). Rotational Freedom, Steric Hindrance, and Protein Dynamics Explain BLU554 Selectivity for the Hinge Cysteine of FGFR4. ACS MEDICINAL CHEMISTRY LETTERS, 10 (8), 1180-1186. 10.1021/acsmedchemlett.9b00196
Other University of Auckland co-authors: Adam Patterson, Martin Middleditch, Jeff Smaill
- Bashiri, G., Grove, T. L., Hegde, S. S., Lagautriere, T., Gerfen, G. J., Almo, S. C., ... Baker, E. N. (2019). The active site of the Mycobacterium tuberculosis branched-chain amino acid biosynthesis enzyme dihydroxyacid dehydratase contains a 2Fe-2S cluster. The Journal of biological chemistry, 294 (35), 13158-13170. 10.1074/jbc.ra119.009498
Other University of Auckland co-authors: Ghader Bashiri
- Myint, K., Biswas, R., Li, Y., Jong, N., Jamieson, S., Liu, J., ... Lu, J. (2019). Identification of MRP2 as a targetable factor limiting oxaliplatin accumulation and response in gastrointestinal cancer. Scientific reports, 9 (1)10.1038/s41598-019-38667-8
Other University of Auckland co-authors: Catherine Han, Stephen Jamieson, Mark McKeage
- Kalyukina, M., Yosaatmadja, Y., Middleditch, M. J., Patterson, A. V., Smaill, J. B., & Squire, C. J. (2019). TAS-120 Cancer Target Binding: Defining Reactivity and Revealing the First Fibroblast Growth Factor Receptor 1 (FGFR1) Irreversible Structure. ChemMedChem, 14 (4), 494-500. 10.1002/cmdc.201800719
Other University of Auckland co-authors: Jeff Smaill, Adam Patterson, Martin Middleditch
- Son, S. J., Huang, R., Squire, C. J., & Leung, I. K. H. (2019). MCR-1: a promising target for structure-based design of inhibitors to tackle polymyxin resistance. Drug discovery today, 24 (1), 206-216. 10.1016/j.drudis.2018.07.004
Other University of Auckland co-authors: Ivanhoe Leung, Renjie Huang
- Cameron, A. J., Squire, C. J., Edwards, P. J., Harjes, E., & Sarojini, V. (2017). Crystal and NMR structures of a peptidomimetic β-turn that provides facile synthesis of 13-membered cyclic tetrapeptides. Chemistry - An Asian Journal, 12 (24), 3195-3202. 10.1002/asia.201701422
Other University of Auckland co-authors: Viji Sarojini, Alan Cameron
- Li, X., Guise, C. P., Taghipouran, R., Yosaatmadja, Y., Ashoorzadeh, A., Paik, W.-K., ... Xu, Y. (2017). 2-Oxo-3, 4-dihydropyrimido[4, 5-d]pyrimidinyl derivatives as new irreversible pan fibroblast growth factor receptor (FGFR) inhibitors. European Journal of Medicinal Chemistry, 135, 531-543. 10.1016/j.ejmech.2017.04.049
Other University of Auckland co-authors: Adam Patterson, Jeff Smaill, Amir Ashoorzadeh
- Badrinarayanan, S., Squire, C. J., Sperry, J., & Brimble, M. A. (2017). Bioinspired total synthesis and stereochemical revision of the fungal metabolite pestalospirane B. Organic letters, 19 (13), 3414-3417. 10.1021/acs.orglett.7b01371
Other University of Auckland co-authors: Jonathan Sperry, Margaret Brimble