We study the general architecture of the replisome in archaea, especially around the essential PolD, that we discovered to be unique among other DNA polymerases, as it has the fold of multi-subunit RNA polymerases.
We are part of the Department of Structural Biology and Chemistry in Institut Pasteur, Paris.
Our main field is Structural Molecular Biology and Biophysics augmented by some techniques of Computational Biology.
We use experimental techniques such as crystallography and cryo-electron microscopy to visualize at the atomic level the structure of molecules essential to life and to understand their functional properties, especially for:
• DNA and RNA polymerases involved in genome replication or transactions (repair, transcription, transposition...)
• Ion channels involved in electric nerve signaling and cell-cell communications.
We complement them with computational approaches such as molecular dynamics (atomic models), normal modes dynamics (coarse-grained models) and statistical thermodynamics, in order to go beyond the essentially static pictures given by these methods.
In addition, computational tools allow to make use of the important information contained in massive sequence data of related molecules in the tree of life and help to understand what is essential in their active site structure and how it is modulated.
As such, homology modelling and molecular phylogeny techniques are routinely used to extend the scope of our studies,
while simulation of the transition path that "connect dots" between different conformational states of these macromolecule help understand the molecular origin and essential features of their function.
We also try to better understand the electrostatics properties of macromolecules and their interaction with the solvent and ligands, in order to predict their binding properties and inspire drug design.
When appropriate we study their structure in the context of their partners in larger macromolecular complexes and try to dissect the molecular interactions between them in order to understand possible emerging collective properties (systems biology).
Our main goal is to understand how these molecular machines work at the atomic level so as to design structure-inspired drugs (pharmacology and drug discovery) and re-design their active site(s) to make them accept other substrates (synthetic biology).
We are developing new computational methods to calculate the electrostatics of proteins, understand their dynamical properties and simulate transitions between two known conformations of the same macromolecule.
We work with archaeal DNA polymerases (PolB) that were evolved to accept xeno-nucleotides to understand the molecular basis of their changed specificity. We use this information to engineer new DNA polymerases to synthesize variants of DNA and RNA.
We study the mechanism of DNA Repair of (DNA) Double Strand Breaks through the so-called Non-Homologous End Joining (NHEJ) process in mammals using x-ray crystallography and structural studies of pol mu and Tdt
Ligand-gated Ion channels
Marc Delarue (PI)
We study the structure and function of ligand-gated ion channels by X-ray crystallography to understand
• the gating mechanism (opening of the pore upon agonist binding)
• the permeation mechanism (transport of ions through the pore)
• modulation by allosteric compounds (general anesthetics, barbiturates…)