Structural Dynamics of Macromolecules - URA 2185 CNRS  


  Annual Report

The aim of the group is to understand at the molecular level the structure and dynamics of proteins of pharmaceutical interest, using X-Ray crystallography and computational structural biology.

Experimental results

a) Archaeal DNA polymerase (coll. G. Henneke, IFREMER)

Crystals of an archaeal DNA polB have been obtained and solved at 3.6 Angstrom resolution, offering the first view of a dimer of a DNA polymerase in the absence of any substrate. We have shown that this dimer is also present in solution. Attempts to get crystals of complexes with DNA are underway.

b) Structural studies of human pol mu (coll. F. Rougeon, I.P.)

Pol mu is a recently discovered DNA polymerase involved in Non-Homologous End-Joining repair system of DNA double-strand breaks. We have shown that pol mu is much more sensitive to limited digestion by various proteases than TdT, its closest homologue in the pol X family, and used this property to probe conformational change in the presence of various substrates. In addition, the activity of 25 different single point mutants in and around the active site of TdT has been characterized. Two mutants were found to display pol mu phenotype. We are extending our studies of the pol X family to bacterial ones.

c) Structural studies of a bacterial homolog of the nicotinic receptor (coll. P.J. Corringer, I.P.)

We have solved the structure of an apparently open form of a bacterial analog of the nicotinic receptor at 2.9 Angstrom resolution; this protein is a proton-gated pentameric cation channel. This was recently published in Nature. We are supplementing this experimental work with Molecular Dynamics simulations, together with Marc Baaden (IBPC, Paris) to try to understand the nature of the open -> close transition.

Computational results

  1. NOMAD-Ref. We have put on-line and regularly updated a variety of refinement tools that use Normal Modes as a reduced set of degrees of freedom to conduct refinement of models with either X-Ray data or cryo-electron microscopy data. Tests are also being conducted with SAXS data.

  2. PDB_Hydro (coll. H. Orland, CEA and P. Koehl, Davis, USA). We have validated a number of new applications of a new method designed to calculate electrostatics properties of macromolecules in a dipolar solvent of variable density, thereby generalizing the Poisson-Boltzmann Equation method.

  3. Conformational transitions (Coll. S. Doniach, Stanford and P. Koehl, Davis). We have pursued our work aiming at producing physically exact trajectories along the reaction pathway between two known structural forms of the same macromolecule (see We have extended it to make it work with full atomic representation of very large macromolecules and complexes (up to 15,000 atoms).

Keywords: Crystallography, membrane receptors, DNA repair, structural transition, drug design


Lindahl E, Delarue M. (2005) Refinement of docked proteinligand and protein DNA structures using low frequency normal mode amplitude optimization. Nucleic Acids Res. 33:4496506.

Delarue M, Duclert-Savatier N, Miclet E, Haouz A, Giganti D, Ouazzani J, Lopez P, Nilges M, Stoven V. (2007) Three dimensional structure and implications for the catalytic mechanism of 6-phosphogluconolactonase from Trypanosoma brucei. J Mol Biol. 366:86881.

Delarue M. (2007) An asymmetric rule in the assignment of codons: possible clue to a quick early evolution of the genetic code through successive binary choices. RNA 13:1619. Epub 2006, Dec 12.

Azuara C, Orland H, Bon M, Koehl P, Delarue M. (2008) Incorporating dipolar solvents with variable density in Poisson-Boltzmann electrostatics. Biophys J. 95:5587605.

Bocquet N, Nury H, Baaden M, Le Poupon C, Changeux JP, Delarue M, Corringer PJ. (2009) X-Ray structure of an apparently open form of a bacterial ligandgated pentameric ion channel. Nature 457:1114. Epub 2008, Nov 5.

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Activity Reports 2009 - Institut Pasteur
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