Structural oncology

This project focuses on target proteins of the Ras family, chosen for their interest in current cancer research. Ras proteins are small GTPases involved in the signal transduction cascade that controls cell proliferation. They present a switch mechanism, cycling between an inactive GDP‑bound and and active GTP-­bound state. When bound to GTP, Ras are switched on and subsequently able to switch on other effector proteins, following RAS in the signal transduction pathway. This activation/inactivation process is mediated by two activators, GAP and GEF, respectively enhancing Ras hydrolysis activity and forcing the release of GDP.
 
Point mutations in RAS occur in 20-­30% of all human tumors. When mutated, Ras undergoes a conformational change that alters its hydrolysis capabilities and its binding affinity with GAP. It consequently remains in it active GTP-­bound state, and causes overactive signaling inside the cell. For this reason, understanding the biomolecular processes that govern Ras activity, as well as mutation effects, present evident benefits for cancer research.

Two ways to prevent from abnormal cell proliferation can be envisaged
 
i) restoring Ras witch mechanism  (i.e. GTP hydrolysis and/or GAP interaction) ii) preventing Ras from binding its effectors.  Proposing solutions to inhibit the mutation effects can only be achieved by investigating the detailed structure/activity relationship of oncogenic mutants, which is possible with the Static Mode approach, developed in our team. This method has already been validated on a wide variety of systems including molecules of interest for oncology such as dihydrofolate reductase. 
We are currently using our software FleXible as a “probe” to explore Ras biomechanical properties at atomic level, and to mechanically simulate the activation/inactivation process. 
 
Our goal is to acquire a unique understanding of the biomolecular processes that govern Ras biological function and mutation effects, and consequently, how to reverse them. Since we are able to simulate custom design modification strategies and to evaluate their impact, we propose to perform the screening of mutations impact in view of guiding mutation experiments, in collaboration with Claudius Regaud - INSERM.
 

We thank RITC foundation for supporting this project (SAMO).