Title:　Structural Analysis of eIF4E Associated with Spliced Leader and its Application for Rational Drug Design.

Speaker:　 Dr. Weizhi Liu

Department of Biochemistry and Molecular Genetics

University of Colorado Health Sciences Center Colorado, US

Host:　 Dr. Xumin Wang

Time: 2:00-3:30 PM. Feb 2, 2010

Location:　 Conference room 202, Beijing Institute of Genomics，CAS

Tittle:  Structural Analysis of eIF4E Associated with Spliced Leader and its Application for Rational Drug Design

Abstract: The parasite cap binding protein (eIF4E) could bind both mono-methylated (MMG) and tri-methylated cap (TMG), however, the mammalian eIF4E could only specifically bind ?MMG. The TMG binding mechanism to parasite eIF4E is still elusive so far. In order to explore this mechanism, a series of biochemical and biophysical techniques were applied, including mutagenesis, fluorescence titration, ITC, NMR and crystallography. Finally we found that parasite eIF4E follows different mechanism for TMG binding and protein dynamics (conformational change) is playing crucial role in TMG binding. Based on this finding, a novel cap analogs derivative was designed and tested, and the result showed both the binding affinity and translation inhibition activity were increased 5×fold compared to the cap analogs. This research not only contributes a lot to the understanding of TMG cap binding mechanism, also provides a promising anti-parasite drug target. Additionally, it also promotes the anti-cancer drug development because eIF4E is an important anti cancer drug target and the TMG analogs provide a natural lead for this target.

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