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Dr James A Irving
Structural Biology Unit / Victorian Bioinformatics Consortium, Dept. Biochemistry and Molecular Biology
Monash University
Clayton Campus, Victoria 3800
Email: james.irving@med.monash.edu.au
Tel: +61-3-9905-3781
Fax: +61-3-9905-4699
Homepage: http://vbc.med.monash.edu.au/~jirving

Structural and Computational Biology of Serpins and Proteases
Much of our research concerns the evolutionary, biochemical and structural aspects of a family of protease inhibitors called 'serpins'. Members of this superfamily are found in all branches of life, from archaea and bacteria to humans, and play a role in a diverse range of processes such as blood coagulation, chromatin condensation, and cell cycle regulation, to name a few. Serpins (along with a viral protein, p35) are unique in that their inhibitory activity is dependent upon a marked conformational transition that occurs upon complex formation with the target protease.
Serpins share a well-conserved tertiary structure; within the context of this scaffold, specialized adaptations have permitted regulation of activity by a wide variety of ligands, increased thermal and chemical stability, and acquisition of ancilliary functions unrelated to protease inhibition. We are particularly interested in investigating the structural basis for characteristics including: (1) The chromatin-condensing ability of the nuclear serpin, MENT; (2) The ability of the serpin maspin to exert tumour-suppressor activity, in spite of an inability to undergo conformational change normally important to serpin function; and (3) The increased thermal stability of serpins from thermophilic organisms, given that mammalian serpins have the propensity to polymerise at elevated temperatures. These projects are being tackled through use of biochemical, biophysical and crystallographic approaches. In addition, we make use of computational techniques such as homology modelling, sequence analysis, and phylogenetic analysis to understand the acquisition of novel features.
Dr. Rob Pike, Monash University
Dr. Jamie Rossjohn, Monash University
Dr. Peter Smooker, Monash University
Dr. Merrill Rowley, Monash University
Dr. Sergei Grigoryev, Penn State University, Hershey, USA
Dr. Margaret Worrall, University College, Dublin, Ireland
Irving JA, Cabrita L, Rossjohn J, Pike RN, Bottomley SP, Whisstock JC.
The 1.5 Å crystal structure of a prokaryote serpin:
controlling conformational change in a heated environment. (2003)
Structure, 11:387-397.

Irving JA, Spithill TW, Pike RN, Whisstock JC, Smooker PM. "The
evolution of enzyme specificity in Fasciola spp." (2003)
Journal of Molecular Evolution, 57:1-15.

Irving JA, Shushanov SS, Pike RN, Popova EY, Bromme D, Coetzer TH,
Bottomley SP, Boulynko IA, Grigoryev SA, and
Whisstock JC. "Inhibitory activity of a heterochromatin-associated
serpin (MENT) against papain-like cysteine proteinases
affects chromatin structure and blocks cell proliferation." (2002)
Journal of Biological Chemistry, 277:13192-13201.

Irving JA, Pike RN, Dai W, Bromme D, Worrall DM, Silverman GA, Coetzer
TH, Dennison C, Bottomley S, and Whisstock
JC. "Evidence that serpin architecture intrinsically supports
papain-like cysteine protease inhibition: engineering
alpha-1-antitrypsin to inhibit cathepsin proteases." (2002)
Biochemistry, 41:4998-5004.

Irving JA, Steenbakkers P, Lesk AM, Op den Camp H, Pike RN, Whisstock
JC. "Serpins in prokaryotes." (2002)
Molecular Biology and Evolution, 19:1881-1890.

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