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Axe 3 : Structure-based design of inhibitors of small G proteins exchange factors

A. Chavanieu1, Guy Subra1, Julien Viaud1

Small G proteins of the Ras superfamily are monomeric proteins able to bind GDP or GTP. This large superfamily of proteins is grouped into subfamilies called Ras, Rho, Ran, Rab, and Arf. In human, approximately 150 of these proteins are expressed and play a major role in a host of cell functions including growth, differentiation, cell motility, cytokinesis, and transport of materials throughout the cell. Small G proteins family are activated by the exchange of the tightly bound GDP nucleotide by GTP, an intrinsically very slow reaction which is activated by guanine nucleotide exchange factors. Many studies involve the abnormal activation of small G proteins in physiopathological contexts. Thus, GEFs seem to be interesting targets to modulate cellular function upstream small G proteins. However, few examples of inhibitors of the activation of small G proteins are described.
Activation of small G proteins of the Arf family is initiated by exchange factors which carry a catalytic Sec7 domain stimulating the dissociation of nucleotide GDP. The exchange reaction of GDP-GTP implies different steps which can be trapped successively by the toxin Brefeldin A, an uncompetitive inhibitor which stabilize the Arf-GDP-Sec7 complex, by the change of an invariant catalytic glutamate, or by the absence of nucleotide.
Recent work on the inhibition of Arf GEFs by Brefeldin A led us to work on a new concept of inhibition called “interfacial inhibition”; in which a protein-protein interaction is stabilized, rather than prevented, by the fixation of a drug at the protein-protein interface. This concept implies that a drug stabilizes a protein-protein complex in a transient state using unbalanced energy conditions of this rearrangement as Achilles’ heel. Thus, a drug having such characteristics represents an alternative to competitive inhibition.
The structure of the exchange intermediate [Δ17]Arf1-GDP-ARNO trapped by the change of the catalytic glutamate in lysine was recently solved by crystallography (PDB code: 1R8S). Using this structure and the concept of interfacial inhibition, we use virtual screening to find small molecules able to trap or modulate this transient complex of the exchange reaction.

Collaborations (GDR Cnrs 2823)
Jacqueline Cherfils
Laboratoire d’Enzymologie et Biochimie Structurales (LEBS), Bat 34, CNRS, UPR 9063, 1 avenue de la Terrasse, 91198 Gif sur Yvette Cedex, France.
Pierre Chardin / Hélène Barelli
Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-UMR 6097, 660 route des Lucioles, 06560 Valbonne, France.
1Centre de Biochimie Structurale, CNRS-UMR5048 INSERM UMR554 UM1, 29 rue de Navacelles, 34093 Montpellier, France



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