个人简介

B.Sc.Phm., University of Toronto (1998) Ph.D., University of Toronto, Ph.D. (2003) PDF, Ontario Cancer Institute (2005-2008) Biophysical chemistry, protein engineering

研究领域

Biophysical chemistry, protein engineering

1. Transcriptional targeting by the ETS superfamily of transcription factors. ETS-family proteins, which regulate the self-renewal and differentiation of hematopoietic and neural stem cells, exemplify how transcription factors with overlapping DNA sequence preferences achieve target gene specificity. Our interest is to understand the mechanism by which structurally homologous transcription factors discriminate DNA target sites, and to establish chemical control of clinically significant ETS-dependent genes. Our work thus far has revealed a high level of mechanistic heterogeneity in ETS/DNA recognition, including previously unrecognized differences in coupling of preferential hydration and conformation dynamics to site binding. In collaboration with Drs. Dave Boykin and David Wilson, we have also identified lead compounds capable of modulating specific ETS/DNA complexes in vivo and are conducting collaborative preclinical studies to evaluate their therapeutic potential in acute myeloid leukemia, systemic sclerosis, and Epstein-Barr viral oncogenesis in model systems. 2. Toxin engineering. Protein therapeutics capable of conditionally targeting multiple molecular markers are emerging targeted therapeutics. My group has recently engineered structural complementation into the catalytic domain of Pseudomonas exotoxin A, a monomeric ADP-ribosyl transferase that specifically inactivates elongation factor 2 and inhibits ribosomal protein synthesis. Unlike complementing systems based on anthrax toxin, which can be triggered only by extracellular stimuli, the exotoxin-based system is able to respond conditionally to intracellular molecular markers. We are developing this engineered toxin as a prodrug for targeting complex cellular phenotypes and as a tool for screening sequence-specific protease libraries. 3. Biophysical development. In support of our laboratory’s and collaborators’ projects, we develop rigorous, computationally efficient techniques for analyzing complex binding models by calorimetric and other biophysical techniques. One particular area of interest is the explicit formulation of isothermal calorimetric titration (ITC) models in terms of native differential equations, an approach that greatly facilitates the analysis of complex binding systems that would otherwise be recalcitrant to ITC. We have applied our methodology to Ca2+ binding by the EF-hand domain of polycystin-2 and are tackling the binding of cyclic dinucleotides to the virulence factors of V. cholerae.

近期论文

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Heterogeneous dynamics in DNA site discrimination by the structurally homologous DNA-binding domains of ETS-family transcription factors. He G, Tolic A, Bashkin JK, Poon GM. Nucleic Acids Res. 2015 Mar 30. pii: gkv267. [Epub ahead of print] PMID: 25824951 Free Article Related citations Select item 25004822 Prodrug applications for targeted cancer therapy. Giang I, Boland EL, Poon GM. AAPS J. 2014 Sep;16(5):899-913. doi: 10.1208/s12248-014-9638-z. Epub 2014 Jul 9. PMID: 25004822 Related citations Select item 24952944 Mechanistic heterogeneity in site recognition by the structurally homologous DNA-binding domains of the ETS family transcription factors Ets-1 and PU.1. Wang S, Linde MH, Munde M, Carvalho VD, Wilson WD, Poon GM. J Biol Chem. 2014 Aug 1;289(31):21605-16. doi: 10.1074/jbc.M114.575340. Epub 2014 Jun 21. PMID: 24952944 Related citations Select item 24359756 An explicit formulation approach for the analysis of calcium binding to EF-hand proteins using isothermal titration calorimetry. Keeler C, Poon G, Kuo IY, Ehrlich BE, Hodsdon ME. Biophys J. 2013 Dec 17;105(12):2843-53. doi: 10.1016/j.bpj.2013.11.017. PMID: 24359756 Free PMC Article Related citations Select item 24211469 Structural complementation of the catalytic domain of pseudomonas exotoxin A. Boland EL, Van Dyken CM, Duckett RM, McCluskey AJ, Poon GM. J Mol Biol. 2014 Feb 6;426(3):645-55. doi: 10.1016/j.jmb.2013.11.002. Epub 2013 Nov 8. PMID: 24211469 Free PMC Article Related citations Select item 24157839 Structure-dependent inhibition of the ETS-family transcription factor PU.1 by novel heterocyclic diamidines. Munde M, Wang S, Kumar A, Stephens CE, Farahat AA, Boykin DW, Wilson WD, Poon GM. Nucleic Acids Res. 2014 Jan;42(2):1379-90. doi: 10.1093/nar/gkt955. Epub 2013 Oct 23. PMID: 24157839 Free PMC Article Related citations Select item 23416556 Probing the electrostatics and pharmacological modulation of sequence-specific binding by the DNA-binding domain of the ETS family transcription factor PU.1: a binding affinity and kinetics investigation. Munde M, Poon GM, Wilson WD. J Mol Biol. 2013 May 27;425(10):1655-69. doi: 10.1016/j.jmb.2013.02.010. Epub 2013 Feb 14. PMID: 23416556 Free PMC Article Related citations Select item 23068040 Quantitative analysis of affinity enhancement by noncovalently oligomeric ligands. Poon GM. Anal Biochem. 2013 Feb 1;433(1):19-27. doi: 10.1016/j.ab.2012.10.005. Epub 2012 Oct 12. PMID: 23068040 Related citations Select item 22533913 DNA binding regulates the self-association of the ETS domain of PU.1 in a sequence-dependent manner. Poon GM. Biochemistry. 2012 May 22;51(20):4096-107. doi: 10.1021/bi300331v. Epub 2012 May 14. PMID: 22533913 Related citations Select item 22474303 Sequence discrimination by DNA-binding domain of ETS family transcription factor PU.1 is linked to specific hydration of protein-DNA interface. Poon GM. J Biol Chem. 2012 May 25;287(22):18297-307. doi: 10.1074/jbc.M112.342345. Epub 2012 Apr 2. PMID: 22474303 Free PMC Article Related citations Select item 20100451 Explicit formulation of titration models for isothermal titration calorimetry. Poon GM. Anal Biochem. 2010 May 15;400(2):229-36. doi: 10.1016/j.ab.2010.01.025. Epub 2010 Jan 25. PMID: 20100451 Related citations Select item 18358491 The catalytic subunit of shiga-like toxin 1 interacts with ribosomal stalk proteins and is inhibited by their conserved C-terminal domain. McCluskey AJ, Poon GM, Bolewska-Pedyczak E, Srikumar T, Jeram SM, Raught B, Gariépy J. J Mol Biol. 2008 Apr 25;378(2):375-86. doi: 10.1016/j.jmb.2008.02.014. Epub 2008 Feb 15. PMID: 18358491 Related citations Select item 18031269 Enhancement of oligomeric stability by covalent linkage and its application to the human p53tet domain: thermodynamics and biological implications. Poon GM. Biochem Soc Trans. 2007 Dec;35(Pt 6):1574-8. Review. PMID: 18031269 Related citations Select item 17965191 A rapid and universal tandem-purification strategy for recombinant proteins. McCluskey AJ, Poon GM, Gariépy J. Protein Sci. 2007 Dec;16(12):2726-32. Epub 2007 Oct 26. PMID: 17965191 Free PMC Article Related citations Select item 17635149 Cell-surface proteoglycans as molecular portals for cationic peptide and polymer entry into cells. Poon GM, Gariépy J. Biochem Soc Trans. 2007 Aug;35(Pt 4):788-93. Review. PMID: 17635149 Related citations Select item 17113101 Tandem dimerization of the human p53 tetramerization domain stabilizes a primary dimer intermediate and dramatically enhances its oligomeric stability. Poon GM, Brokx RD, Sung M, Gariépy J. J Mol Biol. 2007 Jan 26;365(4):1217-31. Epub 2006 Oct 21. PMID: 17113101 Related citations Select item 16442074 The importance of valency in enhancing the import and cell routing potential of protein transduction domain-containing molecules. Sung M, Poon GM, Gariépy J. Biochim Biophys Acta. 2006 Mar;1758(3):355-63. Epub 2005 Dec 21. Review. PMID: 16442074 Free Article Related citations Select item 15610028 Ionic mobilities of duplex and frayed wire DNA in discontinuous buffer electrophoresis: evidence of interactions with amino acids. Poon GM, Abu-Ghazalah RM, Macgregor RB Jr. Biochemistry. 2004 Dec 28;43(51):16337-47. PMID: 15610028 Related citations Select item 14659744 A thermodynamic basis of DNA sequence selectivity by the ETS domain of murine PU.1. Poon GM, Macgregor RB Jr. J Mol Biol. 2004 Jan 2;335(1):113-27. PMID: 14659744 Related citations Select item 14642754 The DNA double helix fifty years on. Macgregor RB, Poon GM. Comput Biol Chem. 2003 Oct;27(4-5):461-7. PMID: 14642754 Related citations