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Developing non-carbohydrate glycomimetics targeted to bacterial lectins – GLYCOMIME
Protein-carbohydrate interactions play a key role in the first step of numerous biological processes, e.g. fertilization and tissue homing of immune cells, but also in infection, inflammation, migration of tumor cells and other pathologies. Pathogenic microorganisms (viruses, bacteria, fungi and par
Super-resolution microscopy through single-molecule localization at cryogenic temperature – Cryo-PALM
A major current difficulty in the development of super-resolution cryogenic temperature microscopy is the absence of fluorescent markers, particularly fluorescent proteins, that are phototransformable effectively at very low temperatures. The main goal of this project will be to design and character
Mechanism of antimicrobial peptide resistance mediated by an ABC transporter coupled to a two-component regulatory system in Streptococcus pneumoniae – SpABC-TCS
Antibiotic resistance is an increasing global public health threat that concerns all major bacterial pathogens and therapeutic drugs. Antimicrobial peptides are an important component of the first line of defense of most living organisms against invading bacteria and are considered as promising alte
Fonctionally relevant conformations of the protein transporter FhaC: probing the lateral opening of a beta barrel in a biological membrane – OPEN_BAR
The Two-Partner Secretion (TPS) pathway is dedicated to the export of large proteins notably serving as virulence factors. The TpsB transporters are transmembrane ß-barrel proteins that secrete their TpsA substrates across the outer membrane of various Gram-negative bacterial pathogens. They belong
Preventing Transcriptional Conflict – PrTxConf
Gene transcription is a tightly regulated process, which is strongly licensed at initiation, extremely processive throughout elongation, and then essentially abruptly stopped at termination. Broadly speaking, transcription termination stops RNA polymerase (RNAP) in its tracks, and from this arrested
Electrophysiology of Cardiac Mitochondria – MITOCARD
The main objective of MITOCARD is to lead to a major progress in the understanding of cardiac physiology by integrating the mitochondrial properties of cell signaling in the comprehensive view of cardiac energetics and rhythm pathologies. It was recently demonstrated that in the heart, in striking c
Time-resolved cryo-EM studies of translation initiation – TREMTI
In all living cells, translation initiation allows accurate selection of the start codon on a messenger RNA, establishing the reading frame of the protein to be synthesized. This essential step universally involves a macromolecular initiation complex (IC) containing the mRNA, the small ribosomal sub
Structure and Function in Amyloid Signaling – SFAS
Amyloids are fibrillar protein aggregates involved in the etiology of a series of neurodegenerative pathologies such as Alzheimer’s and Parkinson’s disease whose medical and social impacts are ever increasing. Recently it was found that these same protein structures can also fulfill biological funct
Elucidating the in vivo mechanism(s) of peroxiredoxins in oxidative stress protection and aging – PrxAGE
A CONTEXT We address the mechanisms of oxidative stress and aging by focusing on the moonlighting enzymes peroxiredoxins (Prx). Prxs were initially described as degrading H2O2 by use of a reactive cysteine (CP), then shown to operate in H2O2 signaling, and later to undergo hyperoxidation of CP by H
Protein translocation across biological membranes – CROSS
Due to its unique location, the plasma membrane has to conciliate two seemingly antagonist tasks, acting as a barrier to maintain cellular homeostasis while allowing the exchange of molecules required for cell health or involved in signalization. Among the latter, Homeoproteins and some Cell-Penetra
Structural and functional characterization of a SKI sub complex in Saccharomyces cerevisiae – SKA
The steady state level of mRNAs results from an equilibrium between their synthesis and their degradation. This equilibrium is highly regulated and adjusts in response to external stimuli. Moreover, quality-control pathways detect defective or undesired transcripts to target them to degradation. Th
Structural insights into yeast retrotransposons DNA integration mechanism at genes transcribed by RNA Polymerase III – INstruc
A) Scientific background and objectives Retroelements replicate by reverse transcription of their RNA genome into a cDNA that is stably integrated into the host-cell genome by their own integrase (IN). Integration does not occur randomly in vivo, revealing a retroelement-specific pattern of prefer
eIF3-mediated ribosome recruitment by histone H4 mRNA during translation initiation – H4translation
Our lab has shown that histone H4 mRNA combines canonical features (cap-dependent translation) with viral strategy (lack of scanning and internal recruitment of initiation factors) during translation initiation (Mol. Cell, 2011). It contains a double stem-loop structure called eIF4E-sensitive elemen
Probing GPCR architecture on living cells using AFM-single molecule force spectroscopy – GRApHICS
G protein coupled receptors (GPCRs) constitute the largest family of cell surface receptors and are involved in all major physiological processes. Nowadays, they represent the targets for ~ 35% of current medicines. However, many GPCR-acting drugs display on-target adverse effects which can temper t
Biochemical and structural basis of iron-sulfur cluster biogenesis to elucidate the molecular function of frataxin – FRATAXUR
Iron-sulfur (Fe-S) clusters are essential prosthetic groups of proteins and defects in their synthesis lead to severe human diseases such as Friedreich’s ataxia, a fatal neurodegenerative and cardiac disease due to impaired expression of frataxin (FXN). Several drugs aiming to restore the level of F
Optical single live cells ultrasonography – EchoCell
Cell mechanics is involved in several fundamental biological processes such as adhesion maturation, migration, differentiation and malignant transformation. The research effort for studying the mechanics of single cells and subcellular components has thus been rapidly growing with significant result
The role of histone H1 and CENP-C in the structure and epigenetic properties of chromatin – Chrom3D
The long-term goal of this project is to elucidate the 3D structural organization of both conventional (non-centromeric) and centromeric forms of chromatin. We have four principal objectives: Objective 1: To understand how linker histone H1 interacts with single nucleosomes. More specifically, we se
Novel Pfrab6 and PfpyrK1 INhibitor TARgeting MALaria – NINTARMAL
Plasmodium is the protozoan parasite responsible for malaria, first parasitic cause of death worldwide. According to the 2015 World Malaria Report, 214 million people were infected by Plasmodium in 2014, leading to 438 000 deaths out of which about 88% occurred in Africa, mainly in children under fi
Kinetics of the Pentose Phosphate Pathway (PPP) using Dissolution Dynamic Nuclear Polarization (D-DNP) – enzypol
The study of enzyme kinetics, and cell metabolism, is central for the understanding of cellular function and metabolic diseases. In case of genetic disorders, the capacity of the cellular enzymes to adapt often determines the severity of the disease. Over five hundred human diseases are due to metab
Fight the global tuberculosis epidemic: Harness cell-to-cell variation to tackle adaptive persistence – PersisTB
Tuberculosis is the deadliest human infection and a major global health threat, claiming nearly 2 million lives a year, against which everyone is vulnerable due to its aerosol transmission. It affects primarily the lungs but can also spread to other body areas. Mycobacterium tuberculosis is capable
Deciphering the effector functions of ST8SIA4 and polysialylation in the immune response of macrophages against Mycobacterium tuberculosis – MacGlycoTB
BACKGROUND: TB was one of the top 10 causes of death worldwide in 2015, responsible for more deaths than HIV and malaria. The successful parasitism of macrophages (MF) by Mycobacterium tuberculosis (Mtb), the etiological agent of TB in humans, reflects the ability of the pathogen to subvert several
Exploiting the biotechnological potential of the unusual archaeal PolD DNA polymerase by unravelling its specificities at the structural level – ARCHAPOL
DNA polymerases (DNAPs) are molecular motors directing the synthesis of DNA from nucleotides. On the basis of their amino acid sequence and structural analysis, DNAPs have been classified into seven families, A, B, C, D, X, Y and reverse transcriptases. In addition to their fundamental biological fu
Molecular clustering as a new regulatory tool for signaling – MCS
Signaling networks play a fundamental role for life: In order to unravel the way in which living organisms perform many vital tasks, one needs an understanding of the design principles of the signaling pathways which are intertwined into such networks. A ubiquitous, general mechanism to control sign
Physics of lipid droplet budding – NANODROP
Lipid droplets (LDs) are the organelles regulating the energy balance in cells. They are the cell’s main lipid reservoirs, play a major role in membrane biogenesis – critical to cell growth and division – and are involved in a number of metabolic and infectious diseases. LDs are similar to oil-in-wa
Structure and function of human ribosome complexes – HumanRibosome
The ribosome is a molecular machinery that comprises two subunits composed of RNAs and proteins where the small subunit is responsible for mRNA decoding and the large subunit catalyses peptide bond formation. Various prokaryotic and eukaryotic ribosome structures have provided important insights int
Antigen presentation by MHCII in cross-presenting dendritic cells. – Help2Kill
The activation of long-lived cytotoxic CD8+ T cell responses is central to protective immunity against viruses and tumours. This type of immune response is activated by antigenic presentation on MHCI at the surface of type 1 DCs (DC1s) after the phagocytosis of dead cells carrying antigen. This proc
Polyphenol-Bearing Probes for Unveiling Polyphenol-Proteins Interactions – Towards Polyphenol-Based Therapeutics? – POLYPHENOLPROT
Polyphenols that are present in dietary plants are claimed to express human health-protecting effects because of their abilities to ameliorate age-related conditions leading to cardiovascular diseases, cancer, neurological and metabolic disorders, as well as skin and bone deteriorations. This is not
Structure-function-activity guided drug-design on Plasmodium falciparum purine metabolizing enzyme targets – PLASMOPUR
Plasmodium falciparum causes the most lethal form of malaria which leads to more than 600,000 deaths worldwide annually, and which remains a major health threat in tropical and subtropical countries with an increasing expansion due to global warming. Indeed, approximately 215 million people in the w
Discovery of allosteric modulators specifically targeting alpha5-containing nAChRs. – NICOFIVE
The nicotinic acetylcholine receptors (nAChRs) are pentameric complexes belonging to the superfamily of pentameric ligand-gated ion channels (pLGICs), mediating excitatory cholinergic communication between cells in the nervous system. In the brain, the major nAChR is made by the association of the a
How partners define Myosin VI function in cells: towards a mechanistic understanding of the cellular roles of Myosin VI – MyoActions
Force generation by molecular motors powers numerous cellular processes. Activated by partners, motors can use this force for distinct mechanistic roles, such as transport, anchoring and track organization. However, the actual action the motor performs upon generating force has not been demonstrated
Mechanistic studies of CO 2 reduction: exploration of the biodiversity of CO dehydrogenases – MeCO2Bio
CO dehydrogenases (CODH) are metalloenzymes that catalyze the reversible reduction of CO2 to CO at very high rates, small overpotentials and with a very high specificity regarding the product of the reaction (only CO is formed, not formate nor oxalate). They are invaluable inspiration sources for de
Microtubule and actin coordination by structural MAPs – MAMAs
In mature neurons, the cytoskeleton plays a crucial role in the formation and activity of synapses, which constitute communication sites between neurons and are composed of pre-synaptic (axon terminals) and post-synaptic (dendritic spines) compartments. Cognitive functions, such as learning and memo
Carb2zyme: Unprecedented chemistry for carbon-carbon bond formation by an emerging class of metallo-enzymes – Carb2zyme
Carbon-carbon bond formation plays an important role in the chemical industry. However, only few methodologies are available for C–C bond formation at unreactive carbon atoms. These methods often require noble metals and stringent experimental conditions which are not compatible with green chemistry
Stable lipid bilayers past the boiling point of water – ArchaeoMembranes
Two major structural adaptations have been linked with the adaptation of the membrane to extreme pH and temperature environments: the synthesis of membrane-spanning, bipolar lipids and the binding of the glycerol moiety and the hydrocarbon chains by an ether bound. Bipolar lipids can form lipid mono
Deciphering the role of poroelasticity in tumor dynamics using multiscale acoustic probing – PoroTume
Despite deeper understanding of cancer metabolism, 90% of experimental drugs fail in clinical studies, mostly due to lack of efficacy. This stems from the lack of predictability of in vitro and in vivo models that are used to design generic drugs at preclinical stages, and from the limited histophys
Deciphering the mechanism of MYcolic acids TRAnsport by MmpL3, a highly valuable drug target for the treatment of tuberculosis – MyTraM
Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis (TB), is one of the deadliest human pathogen. Despite existing chemotherapy, Mtb has been responsible for the death of 1.4 million people and about 10 million new infections in 2015 (WHO report on TB, 2016). This concerns not only
Understanding heme stress sensing system by pathogens, to design new antibiotics – HemeDetox
Heme (the blood hemoglobin cofactor) is a vital but toxic molecule for all organisms. When numerous Gram-positive pathogens are confronted with blood-heme toxicity during infection, they respond by inducing expression of HrtBA, a heme efflux transporter. hrtBA is regulated by HssRS (Heme sensing sys
Structure and activities of SULF extracellular sulfatases – SULFatAS
Heparan sulfate (HS) are complex polysaccharides abundantly found in extracellular matrices and cell surfaces. These polysaccharides participate to major cellular processes through their ability to bind and modulate a wide array of signalling proteins. HS/ligands interactions occur through saccharid
A multidisciplinary and integrative approach for deciphering the assembly, structure and dynamics of a contractile tail baseplate – T6-PLATFORM
Contractile injection machines are fascinating specialized nano-structures evolved by bacterial and viral pathogens to deliver macromolecules into target cells. These machines have been elaborated for different purposes such as the injection of DNA into host cells by bacteriophages or for the delive
Site-selective faithful monitoring at the single molecule level of local changes in nucleic acids – SMFLUONA
Numerous cell mechanisms and pathways rely on dynamic interactions of RNAs or DNAs with proteins that induce local and transient changes in their secondary and tertiary structures. Though structural methods, such as X-ray diffraction, NMR or electron microscopy provide invaluable information on the
MInimal efflux System for studying functional Trans-Envelope tripartite Complexes – MISTEC
Decades of antibiotic overuse to combat infections have led to a dangerous increase of pathogenic bacteria strains resistant to most available antibiotics. Because of a failure in antibacterial drug discovery, antibiotic resistance has therefore emerged as a worldwide public health concern. It becom
Molecular mechanisms of functional disordered C-terminal regions of GPCRs and impact on arrestin signaling pathways – GPCteR
The majority of hormones and neurotransmitters communicate information to cells via G protein-coupled receptors (GPCRs). The large number of biological functions they control also makes these membrane receptors one of the most prominent families of pharmacological targets in biomedicine. GPCRs exhib
Production of recombinant membrane proteins embedded in heterologous caveolae membrane – CAVEOTANK
Membrane proteins (MPs) play crucial roles in a wide variety of cellular processes. They are involved in numerous pathologies and are thus important drug targets. Their overexpression in heterologous systems is necessary for their detailed structural and functional analysis. However this strategy le
Allostery and conformational dynamics in GPCR signaling – allosig
The majority of hormones and neurotransmitters communicate information to cells via G protein-coupled receptors (GPCRs). The large number of biological functions they control also makes these membrane receptors one of the most prominent families of pharmacological targets in biomedicine. GPCRs exhib
Enterobacteria takeover by phage infection – TakeoverBac
At the onset of infection, bacteriophage viruses (or phages) defeat bacterial defenses and hijack cellular functions to propagate inside their hosts. A century after phages were discovered and despite many scientific breakthroughs in phage research, the early mechanisms of host takeover during infec
Chloroplast biogenesis: function, regulation and structure of the plastid-encoded RNA-polymerase complex and its associated proteins PAPs – PEPRegulChloro3D
The major source of renewable bioenergy on Earth comes from the ability of plants to convert sunlight into chemical energy in a chloroplast-dependent process designated as photosynthesis. During this energy conversion, there are consumption of carbon dioxide and release of di-oxygen impacting the Ea
In vivo crystallization: a novel strategy to obtain atomic-resolution insights into protein structure and dynamics at X-ray free-electron lasers and synchrotrons. – X-in-vivo
The advent of X-ray free electron lasers (XFELs) has revolutionized structural biology, opening doors to macromolecular structure determination from nanocrystals and to time-resolved experiments at ultra-fast time-scale (fs-ps). The X-in-vivo project aims at developing an in-vivo crystallization met
from Bacterial Nox to Drug Identification Tools – BANDIT
The NADPH OXidase complex was the first identified system that generates reactive oxygen species in a dedicated manner. NOX are proteins involved in the transmembrane transfer of electrons to the molecular oxygen, resulting in the production of superoxides. Deregulation of Nox-dependant ROS producti
New mechanism of chaperone-assisted gene silencing by trans-acting sRNA – RNAchap
In all domains of life, non-coding RNAs have key roles in the function of the cell (gene silencing, host defense,...). Finding how these RNA species interact with other components of the cell remains a significant challenge. In both eukaryotic and prokaryotic organisms, protein-assisted base pairing
Ligand-directed endogenous receptor labeling: application to the study of D1-mGlu5 heteromers in neurons. – LANTHSLIDER
In this proposal, non-invasive ligand-driven specific fluorescent staining of endogenously expressed membrane receptors will be engineered. Lanthanide complexes will be linked to antagonist of the receptor of interest after which an amino acid close to its binding pocket such as a lysine will be cov