Institut de Biologie StructuraleGrenoble / France

Contact person(s) related to this article / MADERN Dominique

Structure, function, dynamics and evolution within a large family of dehydrogenases

Principal investigator : Dominique Madern

Group members associated : Jennifer Roche, Eric Girard, Jacques Covès, Bruno Franzetti, Giuseppe Zaccaï

How does nature generate new enzyme function, catalytic regulation and appropriate stabilization mechanism to fold properly is a central issue in biology. To address this question, we use a multidisciplinary approach by combining, bioinformatics, biochemistry, structural biology, biophysical characterization and molecular dynamics simulation. Our favorite model enzymes belongs to the large family of malate and lactate dehydrogenases. By using resurrected ancestral enzymes, we can study how the evolutionary trajectories have shaped the various properties of contemporary enzymes. At the final stage of our investigation we would like to investigate molecular motions of ancestral enzymes and modern’s orthologues by neutron spin echo and molecular dynamics simulation.

From left to right : Phylogenetic tree of the LDH/MalDH family. Cations and anions associated to the surface of a modern halophilic malate dehydrogenase. Electrostatic surface representation of a modern halophilic malate dehydrogenase. Ribbon drawing of an ancestral halophilic malate dehydrogenase.


ANR AlloAnc (2017-2020), AlloSpace (2022-2026)


The bioinformatics is done by Pr Céline Brochier-Armanet and Dr Manolo Gouy, (LBBE, Lyon 1 University) and Dr Samuel Blanquart (INRIA Rennes). The dynamics is studied by Dr Marco Maccarini (INAC, Grenoble) and Fabio Sterpone (LBT, Paris), by Paul Schanda (IST-Austria), Roman Lichtenecker (University of Vienna) and Gianluca Santoni (ESRF, Grenoble). The effect of irradiation on activity and conformational stability of extremophilic lactate dehydrogenases is studied in collaboration with Dr Frédéric Halgand and Pr Chantal Houée Levin (LCP, Orsay University).


  • Iorio A, Roche J, Engilberge S, Coquelle N, Girard E, Sterpone F, Madern D. Biochemical, structural and dynamical studies reveal strong differences in the thermal-dependent allosteric behavior of two extremophilic lactate dehydrogenases. J Struct Biol. (2021), 213(3), pp.107769.
  • Brochier-Armanet C, Madern D. Phylogenetics and biochemistry elucidate the evolutionary link between l-malate and l-lactate dehydrogenases and disclose an intermediate group of sequences with mix functional properties. Biochimie. (2021) 191, pp.140-153.
  • Blanquart S, Groussin M, Le Roy A, Szöllosi GJ, Girard E, Franzetti B, Gouy M, Madern D. Resurrection of Ancestral Malate Dehydrogenases Reveals the Evolutionary History of Halobacterial Proteins : Deciphering Gene Trajectories and Changes in Biochemical Properties. Mol Biol Evol. (2021) 38(9), pp.3754-3774.
  • Marina Katava, Marco Maccarini, Guillaume Villain, Alessandro Paciaroni, Michael Sztucki et al. Thermal activation of ’allosteric-like’ large-scale motions in a eukaryotic Lactate Dehydrogenase. Scientific Reports (2017), 7, pp.41092
  • Maria Kalimeri, Eric Girard, Dominique Madern, Fabio Sterpone. Interface matters : the stiffness route to stability of a thermophilic tetrameric malate dehydrogenase. PLoS ONE (2014), 9 (12), pp.e113895
  • Jacques Philippe Colletier, Alexei aleksandrov, Nicolas Coquelle, Sonia Mraihi, Elena Mendoza-Barbera et al. Sampling the conformational ernergy landscape of a hyperthermophilic protein by engineering key substitutions. Mol Biol Evol (2012) 29(6), pp1683-1194.