Research Areas:

Protein NMR and Protein Folding.

Research Interests:

Our general interest is on the elucidation of protein structure-function relationship using Nuclear Magnetic Resonance (NMR), particularly on proteins related to human diseases. An understanding of the role played by a protein in human disease requires a detailed picture of its three-dimensional structure and how it interacts with its target ligand as well as an appreciation of how the structure varies as a function of time due to molecular dynamics. Protein structural and dynamical data obtained will aid the design of protein mutants and subsequent activity or binding assays. Over the past several years, multi-dimensional, multi-nuclear solution NMR spectroscopy has become a powerful technology for obtaining both structural and dynamical information on stable isotope-labeled proteins and protein-ligand systems. Advances in protein labeling strategy (preferential protonation of deuterated proteins) and pulse sequence methodology (TROSY) have also greatly increased the size limit of proteins that can be studied by NMR. In addition to properly folded proteins, NMR is particularly useful in characterizing residual structures found in the unfolded state of proteins. Information on the earliest folding events is essential in understanding the protein-folding pathway.

Protein solution structure determination using multi-dimensional NMR experiments

Current Projects:

Our laboratory is interested in elucidation of NMR solution structure-function relationship of proteins related to human diseases. Understanding of the role played by a protein in human disease (molecular pathology) requires a detailed picture of its three-dimensional structure. The structural data obtained is essential in rational design of drug or therapeutic methods. Three protein-ligand systems related to human diseases are currently being studied in our laboratory: (a) Salmonella typhi PilS protein, the structural pilin of Type IVB pili that are involved in bacterial adherence and invasion of human intestinal epithelial cells mediated by Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and lead to Typhoid fever; (b) Hepatitis C virus (HCV) core protein, a multifunctional protein that forms the nucleocapsid of the virus and affects a lot of cellular processes like transcription, apoptosis, cell transformation, immune response and lipid metabolism of the host; (c) MAP-1 (Modulator of Apoptosis), a novel protein that associates with the proapoptotic Bax and the prosurvival Bcl-XL proteins and mediates caspase-dependent apoptosis in mammalian cells when over-expressed.

Selected Publications:

• Siew Leong Chan, Tan Ching Ong, Yun Feng Gao, Yuen Sung Tiong, De Yun Wang, Fook Tim Chew, and Yu Keung Mok (2008) 'Nuclear Magnetic Resonance structure and IgE epitopes of Blo t 5, a major dust mite allergen', J. Immunology, 181, p. 2586-2596.

• Yong-Hong Zhang, Anirban Bhunia, Kah Fei Wan, Mei Chin Lee, Shing-Leng Chan, Victor C.-K. Yu and Yu-Keung Mok (2006) Chelerythrine and sanguinarine docks at distinct sites on BclXL that are not the classic "BH3 binding cleft", J. Mol. Biol., vol. 364, p. 536-549.

• Siew Leong Chan, Seow Theng Ong, Su Yin Ong, Fook Tim Chew, and Yu Keung Mok (2006) "NMR structure based epitope mapping and modulation of dust mite Group 13 allergen as a hypoallergen", Journal of Immunology, vol. 176, p. 4852-4860.

• Xing-Fu Xu, Yih-Wan Tan, Lam Lam, Jim Hackett, Mingjie Zhang and Yu-Keung Mok (2004) "NMR Structure of a Type IVb Pilin from Salmonella typhi and its Assembly into Pilus", J. Biol. Chem., vol. 279, p. 31599-31605

• Mok, Y-K, Lo, K. W-H & Zhang, M.J., 'Structure of Tctex-1 and its interaction with cytoplasmic dynein intermediate chain', J. Biol. Chem., (2001) 276 (17):14067-14074.

• Mok, Y-K, Elisseeva, E.L., Davidson, A.R. & Forman-Kay, J.D. 'Dramatic stabilization of an SH3 domain by a single substitution: role of the unfolded state', J. Mol. Biol., (2001) 307 (3):913-928.

• Mok, Y-K, Alonso, L.G., Lima, M.T.R., Bycroft, M. & Prat-Gay, G. d. 'Folding of a dimeric b-barrel: residual structure in the urea denatured state of the Human Papillomavirus E2 DNA binding domain', Protein Science, (2000) 9:1-13.

• Mok, Y-K, Kay, L.E. & Forman-Kay, J.D. 'NOE data and structure calculation on a 15 N/deuterated drk SH3 domain demonstrating a compact unfolded state under native conditions', J. Mol. Biol., (1999) 289 (3):619-638.

• Mok, Y-K, Bycroft, M. & Prat-Gay, G. d. 'The dimeric DNA binding domain of the human papillomavirus E2 protein folds through a monomeric intermediate which cannot be native-like', Nature Struct. Biol., (1996) 3:711-717.