Senior Scientist, Princess Margaret Cancer Centre
Keywords: p53, structural biology, structural genomics, DNA damage checkpoint, structural proteomics |
My research interests focus on the structure-function relationships of proteins involved in the control of gene expression, the cell cycle and apoptosis. The goals of our research are to understand at the atomic level the origins of protein-DNA and protein-protein interactions and how these processes are modulated by cofactors, phosphorylation, and protein dynamics. Deregulation of the balance between cell growth and death is a major mechanism of oncogenesis. A knowledge of the three-dimensional structure of proteins involved in these processes will enhance our understanding of the molecular basis of cancer and may also serve as a starting point for the design of therapeutic agents to correct these molecular defects. We use multidimensional nuclear magnetic resonance (NMR) spectroscopy in conjunction with biochemical analysis to study the structures of proteins, protein-DNA and protein-protein complexes in solution. Proteins and pathways under study include the tumor suppressor, p53, and related proteins, the oncogene, c-Myc, and the breast cancer susceptibility protein, BRCA.
With the completion of the sequencing phase of many genome projects, the focus of much genomic research is changing to functional genomics or proteomics: genome-wide efforts to understand the functions of all gene products. We are using structural biology as a tool in functional genomics because protein function derives directly from its 3-dimensional structure, and can often be inferred from structural data when sequence information alone is insufficient. Structural Proteomics involves the large scale, high throughput cloning, expression and structure determination (using both x-ray and NMR).
Application of structural genomics techniques toward human and malaria proteins in order to facilitate structure guided drug discovery and to 'de-orphanize' members of human gene families takes place in The Structural Genomics Consortium: http://www.sgc.utoronto.ca/
- Holowaty MN, Sheng Y, Nguyen T, Arrowsmith C, Frappier L.
Protein interaction domains of the ubiquitin-specific protease, USP7/HAUSP. J Biol Chem. 2003 Nov 28;278 48):47753-61. Epub 2003 Sep 23. PMID: 14506283
- Szymczyna BR, Bowman J, McCracken S, Pineda-Lucena A, Lu Y, Cox B, Lambermon M, Graveley BR, Arrowsmith CH, Blencowe BJ. Structure and function of the PWI motif: a novel nucleic acid-binding domain that facilitates pre-mRNA processing. Genes Dev. 2003 Feb 15;17(4):461-75. PMID: 12600940
- Botuyan MV, Mer G, Yi GS, Koth CM, Case DA, Edwards AM, Chazin WJ, Arrowsmith CH. Solution structure and dynamics of yeast elongin C in complex with a von Hippel-Lindau peptide. J Mol Biol. 2001 Sep 7;312(1):177-86. PMID: 11545595
- Ayed A, Mulder FA, Yi GS, Lu Y, Kay LE, Arrowsmith CH.
Latent and active p53 are identical in conformation. Nat Struct Biol. 2001 Sep;8(9):756-60. PMID: 11524676
- Christendat D, Yee A, Dharamsi A, Kluger Y, Savchenko A, Cort JR, Booth V, Mackereth CD, Saridakis V, Ekiel I, Kozlov G, Maxwell KL, Wu N, McIntosh LP, Gehring K, Kennedy MA, Davidson AR, Pai EF, Gerstein M, Edwards AM, Arrowsmith CH. Structural proteomics of an archaeon. Nat Struct Biol. 2000 Oct;7(10):903-9. PMID: 11017201
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|Maria Amelia Navarrete|
|Maria Amelia Navarrete|
|Rob C Laister|
|Chun-Chieh (Jack) Liao|