| A Specific Non-competitive Inhibitor of a Small G protein/GEF Complex |
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Presentation: P01003 Session: Cheminformatics, Library Design and Virtual HTS - Poster SessionAlain Chavanieu, Julien Viaud, Mahel Zeghouf, Bernard Guibert, Catherine Royer, Jean-Francois Guichou, Jean-Christophe Zeeh, Jacqueline Cherfils, Centre de Biochimie Structurale Presenting Author: Alain Chavanieu, Centre de Biochimie Structurale - France Abnormal activation of small G proteins is involved in several human diseases. Small G proteins are activated by GDP/GTP exchange, which is stimulated by their guanine nucleotide exchange factors (GEFs). Thus, small G protein/GEF complexes appear as emerging targets for interrupting signaling networks regulated by small G proteins in pathological contexts. The activation of small G proteins of the Arf family is initiated by exchange factors which carry a Sec7 catalytic domain stimulating the dissociation of the bound GDP nucleotide. The structure of the Arf1-GDP-ARNO reaction intermediate, trapped by a mutation of the catalytic glutamate, was recently solved by X-ray crystallography (PDB code: 1R8S). Using this structure, a small molecule inhibitor was identified by virtual screening, and was shown to inhibit the exchange reaction in vitro. The results of this study and the kinetic characterization of this inhibition will be presented. |