Sheemei Lok

Research

Associate Professor Lok is one of the recipients for the prestigious National Research Foundation fellowship. Dengue Virus (DENV) infects approximately 100 million people each year. Increased travel, together with global climate change will result in further geographical expansion of the territory of the dengue mosquito vector, Aedes aegypti. There is an urgent need to develop safe and effective dengue therapeutics and vaccine.

sheemeiLok-pnas-dengue
Prof Lok’s recent publication “Human antibodies stop dengue virus by jamming its mechanics” appears in PNAS 111:1670-1671

In vitro experiments have shown that non-neutralizing antibodies can enhance DENV infection of Fc receptor bearing macrophages, one of the natural host cells for the virus. This suggested that the presence of non-neutralizing epitopes in a vaccine could potentially increase the chances that a person who had received the vaccine would develop the severe form of the disease, dengue hemorrhagic fever. For this reason, a more promising approach for engineering an effective DENV vaccine is to focus on including neutralizing epitopes. Thus, mapping of neutralizing epitopes is a necessary component of DENV vaccine research. Furthermore, understanding the neutralization mechanism of antibodies and the entry of DENV into the host cells also could aid in the design of targeted therapeutics.

The research in her laboratory therefore, focuses on the understanding of the pathology of dengue virus infection and the mechanism of neutralization by antibodies and other molecules so as to facilitate the development of suitable vaccines and therapeutics. A combination of molecular, immunological, biochemical and structural techniques (x ray crystallography and cryoEM image reconstruction techniques) will be used to achieve these aims.

Selected Publications

Guntur Fibriansah, Kristie D. Ibarra, Thiam-Seng Ng, Scott A. Smith, Joanne L. Tan, Xin-Ni Lim, Justin S. G. Ooi, Victor A. Kostyuchenko, Jiaqi Wang, Aravinda M. de Silva, Eva Harris, James E. Crowe Jr., Shee-Mei Lok, Cryo-EM structure of an antibody that neutralizes dengue virus type 2 by locking E protein dimers. Science 3 July 2015: Vol. 349 no. 6243 pp. 88-91. DOI: 10.1126/science.aaa8651

Shee-Mei Lok (2014). Human antibodies stop dengue virus by jamming its mechanics. Proceedings of National Academy of Sciences USA. 111:1670-1671.

Victor A. Kostyuchenko, Pau Ling Chew, Thiam-Seng Ng, Shee-Mei Lok (2014). Near-atomic resolution cryo-EM structure of Dengue serotype 4 virus. Journal of Virology. Vol 88: 477-482. (Selected for cover page).

Guntur Fibriansah, Joanne L Tan, Ruklanthi de Alwis, Scott A Smith, Thiam-Seng Ng, Victor A Kostyuchenko, Kristie D Ibarra, Eva Harris, Aravinda de Silva, James E Crowe, Jr and Shee-Mei Lok (2014). A potent anti-dengue human antibody preferentially recognizes the conformation of E protein monomers assembled on the virus surface. EMBO Molecular Medicine. Vol 6: 358-371. (Selected for cover page).

Guntur Fibriansah, Thiam-Seng Ng, Victor A Kostyuchenko, Jaime Lee, Sumarlin Lee, Jiaqi Wang, Shee-Mei Lok (2013). Structural Changes in Dengue Virus When Exposed to a Temperature of 37oC. Journal of Virology, Vol 87:7585-92. (Selected for cover page and article featured in a Nature commentary article).

Victor A Kostyuchenko, Qian Zhang, Joanne L Tan, Thiam-Seng Ng, Shee-Mei Lok (2013). Immature and mature Dengue serotype 1 virus structures provide insight into the maturation process. Journal of Virology. Vol 87:7700-7.

David Veesler, Thiam-Seng Ng, Anoop K.Sendamarai, Brian J Eilers, C Martin Lawrence, Shee-Mei Lok, Mark J Young, John E Johnson and Chi-yu Fu. (2013). Life in the extremes, atomic structure of sulfolobus turreted icosahedral virus. PNAS. Vol 110:5504-5509.

Qian Zhang, Cornelia Hunke, Yin-Hoe Yau, Vernon Seow, Sumarlin Lee, Lukas Bahati Tanner, Xue Li Guan, Markus R Wenk, Guntur Fibriansah, Pau Ling Chew, Petra Kukkaro, Goran Biuković, Pei-Yong Shi, Susana Geifman Shochat, Gerhard Grüber and Shee-Mei Lok. (2012). The stem region of premembrane protein plays an important role in the virus surface protein rearrangement during dengue maturation. Journal of Biological Chemistry. Vol 287:40525-40534.

Ee Ping Teoh, Petra Kukkaro, En Wei Teo, Angeline Lim, Tze Tong Tan, Andy Yip, Wouter Schul, Myint Aung, Victor A Kostyuchenko, Yee Sin Leo, Soh Ha Chan, Kenneth GC Smith, Eng Eong Ooi, D Michael Kemeny, Grace K Tan, Jowin KW Ng, Mah Lee Ng, Sylvie Alonso, Pei Yong Shi, Dale Fisher, Brendon Hanson, Shee-Mei Lok* and Paul A MacAry*. (2012). The Structural Basis for Serotype-Specific Neutralization of Dengue Virus by a Natural Human Antibody. Science Translational Medicine. Vol 4:139 * co-corresponding authors.

Hongping Dong, David C. Chang, Maggie Ho Chia Hua, Siew Pheng Lim, Yok Hian Chionh, Fabian Hia, Yie Hou Lee, Petra Kukkaro, Shee-Mei Lok, Peter C. Dedon, and Pei-Yong Shi. (2012). 2’-O Methylation of Internal Adenosine by Flavivirus NS5 Methyltransferase. PLOS Pathogen.Vol 8(4).

Victor A. Kostyuchenko, Joanita Jakana, Xiangan Liu, Andrew D. Haddow, Myint Aung, Scott C. Weaver, Wah Chiu*, and Shee-Mei Lok*. (2011). The 6Å resolution cryo-EM Barmah Forest virus structure shows detailed transmembrane proteins architecture and interactions. J Virol. 2011 Sep;85(18):9327-33.

Cherrier MV, Kaufmann B, Nybakken GE, Lok SM, Warren J, Chen B, Nelson CA, Holdaway H, Kostyuchenko V, Holdaway HA, Chipman P, Kuhn RJ, Diamond M, Rossmann MG, Fremont D (2009). Structural basis for the preferential recognition of immature flaviviruses by a fusion-loop antibody. EMBO J. 28: 3269-3272.

Li L, Lok SM, Yu IM, Zhang Y, Kuhn RJ, Chen J, Rossmann MG. (2008). Structure of the flavivirus precursor membrane-envelope protein complex and its implication for maturation. Science. 319: 1830-1834.

Lok SM, Kostyuchenko V, Nybakken GE, Holdaway HA, Battisti AJ, Sukupolvi-Petty S, Sedlak D, Fremont DH, Chipman PR, Roehrig JT, Diamond MS, Kuhn RJ, Rossmann MG. (2008). Binding of a neutralizing antibody to dengue virus resulted in an altered arrangement of the surface glycoproteins. Nature Structural and Molecular Biology. 15 (3): 312-317.