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Protein Structure and Dynamics Laboratory

Staff Listings

Associate Professor Ashley Buckle

NHMRC Senior Research Fellow

Tel:
+61 3 9902 9313
Fax:
+61 3 9905 9500
Office:
Room 206, Level 2 Building 77 (STRIP 2)
Email:
ashley.buckle@monash.edu

Our research is aimed at understanding how the structure and dynamics of proteins dictates their function. Current themes include:

A major axis of research focuses on the mechanism of action of proteases involved in human disease. Projects involve structure based inhibitor design using crystallography and computational techniques. Examples include:

The design of inhibitors of human Kallikrein-4 (with Dr Jon Harris, Queensland University of Technology).
Inhibitors of human aminopeptidases (with Professor Ian Smith and Professor Mibel Aguilar).
Inhibitors of malarial aminopeptidases and Dr Sheena McGowan.
Active and inactive proteases from the Scabies mite (with Professor David Kemp and Dr Katja Fischer, QIMR).

We are using X-ray Crystallography, Small Angle X-ray Scattering (SAXS), Surface Plasmon Resonance Imaging (SPRi), Biophysics and Molecular Modelling/Simulation to understand the interaction between the Type 1 Diabetes autoantigen Glutamic Acid Decarboxylase (GAD65) and autoantibodies. In collaboration with A/Prof Merrill Rowley, Prof Malcolm Buckle (CNRS/Ecole Normale Supérieure de Cachan, France), and Dr Daniel Christ (Garvan Institute and University of New South Wales).

Computational and bioinformatics tools for structural biology: in collaboration with Monash e-Research Centre, VeRSI and the Australian Synchrotron, we develop software tools for protein structure determination, and bioinformatics tools and databases for structural biology. Recent highlights include:

TARDIS - the world's first federated repository for raw X-ray diffraction data.
Grid computing to speed up structure determination by X-ray crystallography.
REFOLD: towards understanding why some proteins can be refolded and why others cannot.

We use molecular dynamics simulations to understand the role of conformational change and flexibility in protein function. This demands high performance supercomputing, such as the Monash Sun Grid and Orchard - an 800-core Apple supercomputer cluster at Monash, the largest of its type in the southern hemisphere. Recent projects include:

Dynamics requirements for activity of Dihydrodipicolinate synthase (DHDPS). In collaboration with Professor Juliet Gerrard and utilising BlueFern, the University of Canterbury IBM BlueGene Supercomputer.
Role of dynamics in the autoantigenicity of Glutamic Acid Decarboxylase (GAD65).

For details see our group web pages.

Group Members

Research fellows:
Dr David Hoke
Dr Itamar Kass
Dr Grischa Meyer

Software Engineers:
Mr Steve Androulakis
Mr Mark Bate

PhD students:
Ms Olga Ilyichova
Mrs Bindu Jayakrishnan
Mr Daniel Andrews

Recent Selected Publications

Schmidberger JS, Bate MA, Reboul CF, Androulakis SG, Phan JMN, Whisstock JC, Goscinski WJ, Abramson A, and Buckle AM (2010) MrGrid: A Portable Grid Based Molecular Replacement Pipeline. PLoS One. Apr 6;5(4):e10049.

Konagurthu AS, Reboul CF, Schmidberger JS, Irving, JA, Lesk AM, Stuckey PJ, Whisstock JC, and Buckle AM (2010) MUSTANG-MR Structural Sieving Server: Applications in Protein Structural Analysis and Crystallography. PLoS One. Apr 6;5(4):e10048.

Fenalti G and Buckle AM (2009) Structural Biology of the GAD Autoantigen. Autoimmunity Reviews 9(3):148-52. Epub 2009 May 22.

Swedberg JE, Nigon LV, Reid JC, de Veer SJ, Walpole CM, Stephens CR, Walsh TP, Takayama TK, Hooper JD, Clements JA, Buckle AM & Harris, JM. (2009) Substrate-guided design of a potent and selective kallikrein-related peptidase inhibitor for kallikrein 4. Chemistry & Biology, 16, 633-43.

FischerK,Langendorf CG, Irving JA, Reynolds S, Willis C, Beckham S, Law RHP, Yang S, Bashtannyk-Puhalovich TA, McGowan S, Whisstock JC, PikeRN, KempDJ, and Buckle AM (2009) Structural Mechanisms of Inactivation in Scabies Mite Serine Protease Paralogues. J. Mol. Biol. 390(4):635-45.

Arafat Y, Fenalti G, WhisstockJC, MackayIR, Garcia de la BandaM, RowleyMJ and Buckle AM (2009) Structural Determinants of GAD Antigenicity. Molecular Immunology, 47(2-3):493-505

KaisermanD, BuckleAM, DammePV, IrvingJA, LawRHP, MatthewsAY, Bashtannyk-PuhalovichT, LangendorfCG, ThompsonVandekerckhoveJ, GevaertK, WhisstockJC, BirdPI. (2009) >The structure of granzyme C reveals an unusual mechanism of protease auto-inhibition. Proc. Natl. Acad. Sci. USA 106, 5587-92.

McGowan S, Porter CJ, Lowther J, Stack CM, Golding SJ, Skinner-Adams TS, Trenholme KR, Teuscher F, Donnelly SM, Grembecka J, Mucha A, Kafarski P, Degori R, Buckle AM, Gardiner DL, Whisstock JC, Dalton JP. (2009) Structural basis for the inhibition of the essential Plasmodium falciparum M1 neutral aminopeptidase. Proc. Natl. Acad. Sci. USA. 106, 2537-42.

AndroulakisS, SchmidbergerJ, BateM, DeGoriR, BeitzA, KeongC, CameronR, McGowanS, PorterCJ, Harrison A, Hunter J, MartinJL, KobeB, DobsonRCJ, ParkerMW, WhisstockJC, GrayJ, TreloarA, GroenewegenD, Dickson Nand Buckle AM(2008) Federated repositories of X-ray diffraction images. Acta Crystallogr D Biol Crystallogr. 64, 810-814

Zhang Q, Law RH, Bottomley SP, Whisstock JC and Buckle AM. (2008) A structural basis for loop C-sheet polymerisation in serpins. J. Mol. Biol. 376, 1348-59.

Fenalti G, Hampe CS, Arafat Y, Law RHP, Banga JP, Mackay IR, Whisstock JC, Buckle AM, Rowley MJ. (2008) Clustering of autoantibody and T cell determinants on the structure of the 65 kDa isoform of glutamic acid decarboxylase (GAD65) give an insight into the molecular basis of autoreactivity. Diabetes. 57, 1293-1301.

Rosado, C, Buckle AM et al. (2007) A common fold mediates vertebrate defense and bacterial attack. Science, 317, 1548-51.

Fenalti G, Law RH, Buckle AM et al., (2007) GABA production by glutamic acid decarboxylase is regulated by a dynamic catalytic loop. Nature Structure & Molecular Biology, 14, 280-6.

Chow, M. K., Amin, A. A., Fulton, K. F., Fernando, T., Kamau, L., Batty, C., Louca, M., Ho, S., Whisstock, J. C., Bottomley, S. P., & Buckle, A. M. (2005) The REFOLD database: a tool for the optimization of protein expression and refolding. Nucleic Acids Research. 34, D207-12.