Our research aims to better understand how membrane machines operate at the molecular scale, using structural biology. We mainly work with pentameric neurotransmitter-gated channels, and with the phosphate transporter of Toxoplasma gondii.
Our projects mix state-of-the-art eukaryotic expression systems, solid biochemistry, biophysical characterization, electrophysiology, and structural method like cryo-EM.
Our research is curiosity-driven but focuses on membrane proteins that play crucial roles in health and disease.
Insect pentameric receptors
Current insecticides can target the nervous and muscular systems, cellular respiration, growth and development, and the digestive system. Despite this diversity, most of them are neurotoxic, disrupting synaptic transmission and leading to pest death quite effectively. They represent 70% of the world market (+). There are five main targets in the central nervous system, the nicotinic acetylcholine receptors (nAChRs), the sodium channel, the γ-amino acid type A receptors (GABAAR), acetylcholine esterase and the ryanodine receptor (+), and two of them are the subject of this project. The first one, nAChrs, are the most important target of insecticides with a market share of 29% in 2019, and the second one, GABAARs, is also an important target and had to face the emergence of resistance for the first generation of insecticides.
The structural characterization of these receptors will allow the improvement of current insecticides and will open perspectives for future insecticides. Within the team, we seek to understand the molecular impact of current insecticides on insect nAChRs and GABAARs. In practice, we express, purify and visualize by cryoEM some receptors in complex with representative insecticides. In parallel to this project, we are working on the implementation of a platform for screening peptides affecting the receptors we study via yeast displays. This part of our research could lead to the development of more specific and degradable insecticides for the environment.
Francois Dehez et Chris Chipot (LIA, Nancy)
Pierre Charnet (IBMM, Montpellier)
The pentameric serotonin receptor, 5HT3
In the nervous system, pLGICs mediate fast neurotransmission. They function as allosteric signal transducers across the plasma membrane: upon binding neurotransmitter molecules, they undergo complex conformational transitions that result in transient openings of an intrinsic ion channel. The family comprises receptors activated by glycine, GABA, acetylcholine, and serotonin. We aim to reveal the operation mechanism(s) of pLGICs, decipher their conformational transitions, to understand their pharmacology. We have obtained results mostly with the serotonin 5-HT3 receptor.
In recent years, we obtained an X-ray structure of the 5-HT3 receptor in a complex with inhibitory nanobodies (Hassaine et al, Nature 2014) and several cryo-EM structures of the same receptor in different conformations (Polovinkin et al., Nature 2018) stabilized by small molecules (agonists, clinical antagonists, modulators, …).
Francois Dehez et Chris Chipot (LIA, Nancy)
Ghérici Hassaine (Theranyx, Marseille)
Anders Jensen (Department of drug design and pharmacology, University of Copenhagen, Copenhague)
CNRS, CEA, UGA, Marie Curie actions (CIG 631416), ERC (Starting Grant PentaBrain), FRM
APT, the Apicoplast Phosphate Transporter from T.gondii , E.Pebay-Peyroula
Plasmodium and Toxoplasma gondii are obligate intracellular parasites that harbor a plastid, the apicoplast, which is responsible for vital functions such as fatty acid synthesis and isoprenoid synthesis. The import of the essential substrates for these pathways is relying on the solely characterized transporter of the apicoplast of T. gondii and Plasmodium: APT. APT belongs to the family of triosephosphate/phosphate transporters found in plant chloroplasts. It was shown that the disruption of the APT gene in T. gondii leads to the immediate death of the parasite. Our project aims at solving the structure of APT, at atomic resolution by X-ray crystallography. Since 2015, we set up production protocols and characterization technics (thermal stability, transport properties,...). More recently, we exploit nanobodies to stabilize single conformations and enhance the chances to get crystals.
K. Fischer (AMB, UiT Tromsø)
C. Botté (IAB, UGA Grenoble)
H. Hassanzadeh (VIB, Brussels)
A list of Ph.Ds. in the group can be found here.
The complete list of our publications is available here.
Work with us
If you are interested in our research, get in contact with Hugues or Eva. Applications from scientists who like their job with passion and do it with rigor, at any career stage, will be considered with care.