Institut de Biologie StructuraleGrenoble / France

Contact person(s) related to this article / GIRARD Eric

Molecular glues for structural biology

Principal investigator : Eric Girard

Persons involved : Zaynab Alsalman, Bruno Franzetti, Frank Gabel, Jacques Covès

Macromolecular crystallography (MX) is the most widely used method for determining the molecular structure of proteins and obtaining structural information at the atomic level. However, protein crystallography suffers from some major drawbacks : the production of well-diffracting crystals and the phasing process. Among the two, the unpredictability of the crystallization process represents the main bottleneck.

This project started with the development and the use of lanthanide complexes for phasing purpose as lanthanides possess a large anomalous contribution. This first set of complexes allowed to solve the structure of several proteins including large molecular systems (see Hall of fames).

The analysis of the binding of these molecules at the proteins surface provide us with supramolecular interactions involved. For that, we used a combined approach including crystal structure based analysis at high resolution, computational methods (DFT calculations) and in-solution measurements. This sets the foundation of the design of new molecules with improved properties.

In 2014, in collaboration with the team of Olivier Maury (ENS-Lyon), we designed and synthetized a new family of lanthanide complexes we named Crystallophore, Xo4 (Patent : WO12017103545), which combines nucleating, phasing and luminescent properties. Xo4 is thus an unprecedented additive for biocrystallography since it overcomes the two main bottleneck of MX, in particular the crystallization step. Indeed, thanks to its versatility, Xo4 acts as a molecular glue and displays an exceptional capacity to induce crystallization by increasing the number of crystallization conditions and by providing new unique conditions. Xo4 also conserves the high-phasing power of the first generation of complexes as it possesses a lanthanide ion. For structures solved with the crystallophore approach, see Hall of Fame below.

Figure 1 : A few examples of 1st generation Lanthanide complexes / Tb-Xo4 molecule / Example of crystals obtained for the same protein without and with Tb-Xo4 / Structure of the archaeal acetoacetyl-CoA thiolase/HMG-CoA synthase complex (Vögeli et al, PNAS, 2018)

Funding :

  • 2014-2017 : ANR “Ln23” – ANR-13-BS07-0007-02
  • 2015-2016 : Innovation grant – SATT Pulsalys Lyon
  • 2018-2021 : Pack Ambition Recherche – Région Auvergne Rhône Alpes

Collaborations :

Hall of fames :

Structures solved thanks to first lanthanide complexes generation :
PDB_ID1 etc…

Structures solved thanks to crystallophores :
PDB_ID1 etc…

Selected Publications :

  •  The multicatalytic compartment of propionyl-CoA synthase sequesters a toxic metabolite. Iria Bernhardsgrütter, Bastian Vögeli, Tristan Wagner, Dominik Peter, Niña Socorro Cortina, Jörg Kahnt, Gert Bange, Sylvain Engilberge, Eric Girard, François Riobé, Olivier Maury, Seigo Shima, Jan Zarzycki, Tobias Erb. Nature Chemical Biology, Nature Publishing Group, 2018, 14, pp. 1127 - 1132.
  •  Unveiling the Binding Modes of the Crystallophore, a Terbium-based Nucleating and Phasing Molecular Agent for Protein Crystallography. Sylvain Engilberge, François Riobé, Tristan Wagner, Sebastiano Di Pietro, Cécile Breyton, Bruno Franzetti, Seigo Shima, Eric Girard, Elise Dumont, Olivier Maury. Chemistry - A European Journal, Wiley-VCH Verlag, 2018, 24 (39), pp. 9739 - 9746.
  •  Archaeal acetoacetyl-CoA thiolase/HMG-CoA synthase complex channels the intermediate via a fused CoA-binding site. Bastian Vögeli, Sylvain Engilberge, Eric Girard, François Riobé, Olivier Maury, Tobias Erb, Seigo Shima, Tristan Wagner. Proceedings of the National Academy of Sciences of the United States of America , National Academy of Sciences, 2018, 115 (13), pp. 3380 - 3385.
  •  Crystallophore : a versatile lanthanide complex for protein crystallography combining nucleating effects, phasing properties, and luminescence. Sylvain Engilberge, François Riobé, Sebastiano Di Pietro, Louise Lassalle, Nicolas Coquelle, Charles-Adrien Arnaud, Delphine Pitrat, Jean-Christophe Mulatier, Dominique Madern, Cécile Breyton, Olivier Maury, Eric Girard. Chemical Science, The Royal Society of Chemistry, 2017, 8 (9), pp. 5909 - 5917.