Marc Delarue

Marc Delarue
Institut Pasteur International Network · Department of Structural Biology and Chemistry of Paris

Ph D

About

193
Publications
14,538
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11,127
Citations
Citations since 2016
63 Research Items
3152 Citations
20162017201820192020202120220100200300400
20162017201820192020202120220100200300400
20162017201820192020202120220100200300400
20162017201820192020202120220100200300400

Publications

Publications (193)
Preprint
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Replication Protein A (RPA) is a heterotrimeric single stranded DNA-binding protein with essential roles in DNA replication, recombination and repair, in both eukaryotic and archaeal cells. By using an integrative approach that combines three crystal structures, four cryo-EM structures in complex with single-stranded DNA (ssDNA) of different length...
Preprint
Replication Protein A (RPA) is a heterotrimeric single stranded DNA-binding protein with essential roles in DNA replication, recombination and repair, in both eukaryotic and archaeal cells. By using an integrative approach that combines three crystal structures, four cryo-EM structures in complex with single-stranded DNA (ssDNA) of different length...
Article
Full-text available
All genetic information in cellular life is stored in DNA copolymers composed of four basic building blocks (ATGC-DNA). In contrast, a group of bacteriophages belonging to families Siphoviridae and Podoviridae has abandoned the usage of one of them, adenine (A), replacing it with 2-aminoadenine (Z). The resulting ZTGC-DNA is more stable than its AT...
Article
Extracting dynamical pairwise correlations and identifying key residues from large molecular dynamics trajectories or normal-mode analysis of coarse-grained models are important for explaining various processes like ligand binding, mutational effects, and long-distance interactions. Efficient and flexible tools to perform this task can provide new...
Article
Full-text available
Cyanophage S-2L is known to profoundly alter the biophysical properties of its DNA by replacing all adenines (A) with 2-aminoadenines (Z), which still pair with thymines but with a triple hydrogen bond. It was recently demonstrated that a homologue of adenylosuccinate synthetase (PurZ) and a dATP triphosphohydrolase (DatZ) are two important pieces...
Article
Coarse-grained normal mode analyses of protein dynamics rely on the idea that the geometry of a protein structure contains enough information for computing its fluctuations around its equilibrium conformation. This geometry is captured in the form of an elastic network (EN), namely a network of edges between its residues. The normal modes of a prot...
Preprint
Full-text available
Cyanophage S-2L is known to profoundly alter the biophysical properties of its DNA by replacing all adenines (A) with 2-aminoadenines (Z), which still pair with thymines but with a triple hydrogen bond. It was recently demonstrated that a homologue of adenylosuccinate synthase (PurZ) and a dATP triphosphohydrolase (DatZ) are two important pieces of...
Article
Full-text available
To stop the COVID-19 pandemic due to the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which caused more than 2.5 million deaths to date, new antiviral molecules are urgently needed. The replication of SARS-CoV-2 requires the RNA-dependent RNA polymerase (RdRp), making RdRp an excellent target for antiviral agents. RdRp is a multi-s...
Article
Full-text available
Bacteriophages have long been known to use modified bases in their DNA to prevent cleavage by the host’s restriction endonucleases. Among them, cyanophage S-2L is unique because its genome has all its adenines (A) systematically replaced by 2-aminoadenines (Z). Here, we identify a member of the PrimPol family as the sole possible polymerase of S-2L...
Preprint
Full-text available
We present an extension of the Poisson-Boltzmann model in which the solute of interest is immersed in an assembly of self-orienting Langevin water dipoles, anions, cations, and hydrophobic molecules, all of variable densities. Interactions between charges are controlled by electrostatics, while hydrophobic interactions are modeled with a Yukawa pot...
Article
Optimal transport (OT) has become a discipline by itself that offers solutions to a wide range of theoretical problems in probability and mathematics with applications in several applied fields such as imaging sciences, machine learning, and in data sciences in general. The traditional OT problem suffers from a severe limitation: its balance condit...
Article
Full-text available
Archaeal DNA polymerases from the B-family (polB) have found essential applications in biotechnology. In addition, some of their variants can accept a wide range of modified nucleotides or xenobiotic nucleotides, such as 1,5-anhydrohexitol nucleic acid (HNA), which has the unique ability to selectively cross-pair with DNA and RNA. This capacity is...
Article
Full-text available
GLIC is a bacterial homologue of the pentameric ligand-gated ion channels (pLGICs) that mediate the fast chemical neurotransmission of nerve signalling in eukaryotes. Because the activation and allosteric modulation features are conserved among prokaryotic and eukaryotic pLGICs, GLIC is commonly used as a model to study the allosteric transition an...
Article
Pentameric ligand-gated ion channels (pLGICs) are allosteric receptors that mediate rapid electrochemical signal transduction in the animal nervous system through the opening of an ion pore upon binding of neurotransmitters. Orthologs have been found and characterized in prokaryotes and they display highly similar structure–function relationships t...
Article
Full-text available
Replicative DNA polymerases (DNAPs) have evolved the ability to copy the genome with high processivity and fidelity. In Eukarya and Archaea, the processivity of replicative DNAPs is greatly enhanced by its binding to the proliferative cell nuclear antigen (PCNA) that encircles the DNA. We determined the cryo-EM structure of the DNA-bound PolD-PCNA...
Preprint
Full-text available
Replicative DNA polymerases (DNAPs) have evolved the ability to copy the genome with high processivity and fidelity. In Eukarya and Archaea, the processivity of replicative DNAPs is greatly enhanced by its binding to the proliferative cell nuclear antigen (PCNA) that encircles the DNA. We determined the cryo-EM structure of the DNA-bound PolD-PCNA...
Article
Optimal transport (OT) has become a discipline by itself that offers solutions to a wide range of theoretical problems in probability and mathematics. Despite its appealing theoretical properties, solving the OT problem involves the resolution of a linear program whose computational cost can quickly become prohibitive whenever the size of the probl...
Article
Originally defined for the optimal allocation of resources, optimal transport (OT) has found many theoretical and practical applications in multiple domains of science and physics. In this Letter we develop a new method for solving the discrete version of this problem using techniques derived from statistical physics. We derive a strongly concave f...
Article
Full-text available
Eukaryotic DNA polymerase (Pol) X family members such as Pol μ and terminal deoxynucleotidyl transferase (TdT) are important components for the nonhomologous DNA end-joining (NHEJ) pathway. TdT participates in a specialized version of NHEJ, V(D)J recombination. It has primarily non-templated polymerase activity, but can take instructions across str...
Article
RNA aptamers have several advantages over DNA aptamers due to their propensity to fold into three-dimensional structures. However, the synthesis of large RNA libraries remains a challenge as it requires more precautions to conserve their functional integrity, especially when such libraries are intended for aptamers or ribozymes selection. Here, we...
Article
Full-text available
PolD is an archaeal replicative DNA polymerase (DNAP) made of a proofreading exonuclease subunit (DP1) and a larger polymerase catalytic subunit (DP2). Recently, we reported the individual crystal structures of the DP1 and DP2 catalytic cores, thereby revealing that PolD is an atypical DNAP that has all functional properties of a replicative DNAP b...
Article
Replicative DNA polymerases are nano-machines essential to life, which have evolved the ability to copy the genome with high fidelity and high processivity. In contrast with cellular transcriptases and ribosome machines, which evolved by accretion of complexity from a conserved catalytic core, no replicative DNA polymerase is universally conserved....
Article
Full-text available
Residues in proteins that are in close spatial proximity are more prone to covariate as their interactions are likely to be preserved due to structural and evolutionary constraints. If we can detect and quantify such covariation, physical contacts may then be predicted in the structure of a protein solely from the sequences that decorate it. To car...
Article
Full-text available
The pentameric ligand-gated ion channel (pLGIC) from Gloeobacter violaceus (GLIC) has provided insightful structure–function views on the permeation process and the allosteric regulation of the pLGICs family. However, GLIC is activated by pH instead of a neurotransmitter and a clear picture for the gating transition driven by protons is still lacki...
Article
While structural data on viruses are more and more common, information on their dynamics is much harder to obtain as those viruses form very large molecular complexes. In this paper, we propose a new method for computing the coarse-grained normal modes of such supra-molecules, NormalGo. A new formalism is developed to represent the Hessian of a qua...
Article
Full-text available
Connecting the dots among the amino acid sequence of a protein, its structure, and its function remains a central theme in molecular biology, as it would have many applications in the treatment of illnesses related to misfolding or protein instability. As a result of high-throughput sequencing methods, biologists currently live in a protein sequenc...
Article
Full-text available
Nucleic acid aptamers, especially RNA, exhibit valuable advantages compared to protein therapeutics in terms of size, affinity and specificity. However, the synthesis of libraries of large random RNAs is still difficult and expensive. The engineering of polymerases able to directly generate these libraries has the potential to replace the chemical...
Article
Terminal deoxynucleotidyltransferase (TdT) is a member of the polX family which is involved in DNA repair. It has been known for years as an untemplated DNA polymerase used during V(D)J recombination to generate diversity at the CDR3 region of immunoglobulins and T-cell receptors. Recently, however, TdT was crystallized in the presence of a complet...
Article
Full-text available
Significance Pentameric ligand-gated ion channels (pLGICs) mediate fast signal transduction in animal nerve cells through neurotransmitters. Mutation of some of these receptors in the brain causes severe nervous system diseases. The high sequence diversity of prokaryotic receptors makes them unique model systems to understand evolutionary conservat...
Article
Full-text available
Ion channel modulation by general anesthetics is a vital pharmacological process with implications for receptor biophysics and drug development. Functional studies have implicated conserved sites of both potentiation and inhibition in pentameric ligand-gated ion channels, but a detailed structural mechanism for these bimodal effects is lacking. The...
Article
Full-text available
We present a new educational initiative called Meet-U that aims to train students for collaborative work in computational biology and to bridge the gap between education and research. Meet-U mimics the setup of collaborative research projects and takes advantage of the most popular tools for collaborative work and of cloud computing. Students are g...
Article
Full-text available
The Gloeobacter violaceus ligand-gated ion channel (GLIC) has been extensively studied by X-ray crystallography and other biophysical techniques. This provided key insights into the general gating mechanism of pentameric ligand-gated ion channel (pLGIC) signal transduction. However, the GLIC is activated by lowering the pH and the location of its p...
Data
Crystallographic statistics. (DOCX)
Data
Normalized crystallographic ΔCα distance and RMSD values. (A) Normalized Cα distance values (ΔCα/ΔCαctrl) for the remaining resolved structures not shown in Fig 6. The reference values of PDB IDs: 3EAM and 4HFI are shown with each group of structures. (B) Normalized RMSD for each residue (excluding the mutated residue) between all resolved mutant s...
Data
Electrophysiological values. (DOCX)
Data
Comparison of E35 structural conformation between pH 7 and pH 4 structures. (A) Peripheral view facing towards the vestibule and (B) 90° rotation to show the side orientation of the ECD-TMD interface around E35. E35 is shown in stick representation for the GLIC Wt pH 7 (PDB ID: 4NPQ, pink) and pH 4 (PDB ID: 4HFI, black) structures. Residues within...
Article
We propose a novel stochastic method to generate Brownian paths conditioned to start at an initial point and end at a given final point during a fixed time tf under a given potential U(x). These paths are sampled with a probability given by the overdamped Langevin dynamics. We show that these paths can be exactly generated by a local stochastic par...
Article
Significance High-resolution structures of pentameric ligand-gated ion channels have created an opportunity to discover the mechanisms of rapid synaptic transduction in the brain. This study describes the mechanisms of allosteric channel gating using string method simulations, applied to a complete atomistic ion channel, combined with a transition...
Article
Understanding the dynamics of biomolecules is the key to understanding their biological activities. Computational methods ranging from all-atom molecular dynamics simulations to coarse-grained normal mode analyses based on simplified elastic networks provide a general framework to studying these dynamics. Despite recent successes in studying very l...
Article
Full-text available
Key steps in the life cycle of a virus, such as the fusion event as the virus infects a host cell and its maturation process, relate to an intricate interplay between the structure and the dynamics of its constituent proteins, especially those that define its capsid, much akin to an envelope that protects its genomic material. We present a comprehe...
Article
Full-text available
Barbiturates induce anesthesia by modulating the activity of anionic and cationic pentameric ligand-gated ion channels (pLGICs). Despite more than a century of use in clinical practice, the prototypic binding site for this class of drugs within pLGICs is yet to be described. In this study, we present the first X-ray structures of barbiturates bound...
Article
Full-text available
We propose a novel stochastic method to generate Brownian paths conditioned to start at an initial point and end at a given final point during a fixed time $t_{f}$ under a given potential $U(x)$. These paths are sampled with a probability given by the overdamped Langevin dynamics. We show that these paths can be exactly generated by a local Stochas...
Article
Full-text available
Archaeal replicative DNA polymerase D (PolD) constitute an atypical class of DNA polymerases made of a proofreading exonuclease subunit (DP1) and a larger polymerase catalytic subunit (DP2), both with unknown structures. We have determined the crystal structures of Pyrococcus abyssi DP1 and DP2 at 2.5 and 2.2 Å resolution, respectively, revealing a...
Data
Supplementary Figures 1-10, and Supplementary References.
Article
Eukaryotic DNA polymerase of the polX family, such as pol μ and terminal deoxynucleotidyl transferase (TdT), are key components of the non-homologous end-joining or V(D)J recombination machinery, respectively. The established role of TdT is to add random nucleotides during V(D)J recombination. Here we show that TdT also has a templated-polymerase a...
Article
Full-text available
We present a method aimed at sampling charge density fluctuations in Coulomb systems. The derivation follows from a functional integral representation of the partition function in terms of charge density fluctuations. Starting from the mean-field solution given by the Poisson-Boltzmann equation, an original approach is proposed to numerically sampl...
Article
Pentameric ligand-gated ion channels have been identified as the principal target of general anesthetics (GA), whose molecular mechanism of action remains poorly understood. Bacterial homologs, such as the Gloeobacter violaceus receptor (GLIC), have been shown to be valid functional models of GA action. The GA bromoform inhibits GLIC at submillimol...
Article
Full-text available
GLIC receptor is a bacterial pentameric ligand-gated ion channel whose action is inhibited by xenon. Xenon has been used in clinical practice as a potent gaseous anaesthetic for decades, but the molecular mechanism of interactions with its integral membrane receptor targets remains poorly understood. Here we characterize by X-ray crystallography th...
Article
Pentameric ligand-gated ion channels (pLGICs) play essential roles in the transmission and interpretation of synaptic signals. The recent solution of multiple X-ray structures of pLGICs has allowed detailed examination of the molecular mechanisms of synaptic transduction at the atomic level. We have described the mechanism of activation for the pro...
Article
Full-text available
Eukaryotic DNA polymerase mu of the PolX family can promote the association of the two 3'-protruding ends of a DNA double-strand break (DSB) being repaired (DNA synapsis) even in the absence of the core non-homologous end-joining (NHEJ) machinery. Here, we show that terminal deoxynucleotidyltransferase (TdT), a closely related PolX involved in V(D)...
Article
Full-text available
Pentameric ligand-gated ion channels (pLGICs) mediate fast chemical neurotransmission of nerve signalling in the central and peripheral nervous systems. GLIC is a bacterial homologue of eukaryotic pLGIC, the X-ray structure of which has been determined in three different conformations. GLIC is thus widely used as a model to study the activation and...
Article
Full-text available
Significance Pentameric ligand-gated ion channels (pLGICs) mediate neuronal communication in the central nervous system. Upon the neurotransmitter binding, these receptors undergo a rapid conformational change to open an integral ion channel. Mutations impairing the function of pLGICs are known to cause hyperekplexic, myasthenic, and epileptic synd...
Article
Methods for computing electrostatic interactions often account implicitly for the solvent, due to the much smaller number of degrees of freedom involved. In the Poisson–Boltzmann (PB) approach the electrostatic potential is obtained by solving the Poisson–Boltzmann equation (PBE), where the solvent region is modeled as a homogeneous medium with a h...
Article
Background: Pentameric ligand-gated ion channels (pLGICs) mediate fast chemical transmission of nerve signals in the central and peripheral nervous system. On the functional side, these molecules respond to the binding of a neurotransmitter (glycine, GABA, acetylcholine or 5HT3) in the extracellular domain (ECD) by opening their ionotropic pore in...
Article
The Poisson-Boltzmann (PB) formalism is one of the most popular approaches to modeling the solvation of molecules. It assumes a continuum model for water, leading to a dielectric permittivity that depends on regions of space (inside or outside the solute). In contrast, the dipolar Poisson-Boltzmann-Langevin (DPBL) formalism follows a grid-based app...
Article
Pentameric ligand-gated ion channels (pLGIC) mediate fast chemical transmission of nerve signals. The structure of GLIC, a bacterial proton-gated homolog, has been established in its open and Locally Closed (LC) conformations at acidic pH. Here we report its crystal structure at neutral pH, revealing for the first time the two end-points of the gat...
Article
Sauguet et al. recently solved the structure of the pentameric ligand-gated ion channel GLIC in complex with the general anesthetic bromoform [1]. This structure highlights three binding sites in an intra-subunit cavity close to the propofol and desflurane binding sites previously described by Nury et al. [2]. Additionally, a F238A (F14'A) mutant r...
Article
Pentameric ligand-gated ion channels (pLGIC) mediate fast chemical transmission of nerve signals. The structure of GLIC, a bacterial proton-gated homolog, has been established in its open and Locally Closed (LC) conformations at acidic pH. Here we report a new crystal form where the LC and open conformations coexist as discrete forms at acidic pH....
Article
Full-text available
We previously showed (Li, L., and Carter, C. W., Jr. (2013) J. Biol. Chem. 288, 34736–34745) that increased specificity for tryptophan versus tyrosine by contemporary Bacillus stearothermophilus tryptophanyl-tRNA synthetase (TrpRS) over that of TrpRS Urzyme results entirely from coupling between the anticodon-binding domain and an insertion into th...
Article
Full-text available
Significance We describe the X-ray structures of the same pentameric ligand-gated ion channel (pLGIC) in both its liganded or ligand-free conformations. This provides the molecular basis for understanding the opening and closing (gating mechanism) of these key players in the fast transmission of chemical signals at synapses. As described with class...
Article
Terminal deoxynucletidyl transferase (TdT) is overexpressed in some cancer types, where it might compete with pol μ driving the mutagenic repair of double strand breaks (DSBs) through the non homologous end joining (NHEJ) pathway. Here we report the discovery and characterization of pyrrolyl and indolyl diketo acids that specifically target TdT and...