A5031052217- HIV Research and Treatment
- Cytomegalovirus and herpesvirus research
- HIV/AIDS drug development and treatment
- Biochemical and Molecular Research
- Bacteriophages and microbial interactions
- Plant Virus Research Studies
- RNA and protein synthesis mechanisms
- Influenza Virus Research Studies
- Monoclonal and Polyclonal Antibodies Research
- Virus-based gene therapy research
- Enzyme Structure and Function
- Viral Infections and Immunology Research
- RNA modifications and cancer
- Microbial Metabolism and Applications
- Antimicrobial Resistance in Staphylococcus
- Poxvirus research and outbreaks
- T-cell and Retrovirus Studies
- Viral-associated cancers and disorders
- interferon and immune responses
- RNA Interference and Gene Delivery
- Advanced biosensing and bioanalysis techniques
- CRISPR and Genetic Engineering
- Folate and B Vitamins Research
- Microbial Natural Products and Biosynthesis
- Evolution and Genetic Dynamics
Centre National de la Recherche Scientifique
2010-2024
Institut de Biologie Structurale
2021-2024
Université Grenoble Alpes
2021-2024
Institut des Sciences Biologiques
2022-2024
CEA Grenoble
2023
Commissariat à l'Énergie Atomique et aux Énergies Alternatives
2023
The Francis Crick Institute
2017-2022
Harvard University
2013-2016
Dana-Farber Cancer Institute
2016
Université Claude Bernard Lyon 1
2009-2013
Integration is essential for HIV-1 replication, and the viral integrase (IN) protein an important therapeutic target. Allosteric IN inhibitors (ALLINIs) that engage dimer interface at binding site host lens epithelium-derived growth factor (LEDGF)/transcriptional coactivator p75 are emerging class of small molecule antagonists. Consistent with inhibition a multivalent drug target, ALLINIs display steep antiviral dose–response curves ex vivo. multimerize concordantly block its assembly DNA in...
Retroviral integrase (IN) functions within the intasome nucleoprotein complex to catalyze insertion of viral DNA into cellular chromatin. Using cryo-electron microscopy, we now visualize functional maedi-visna lentivirus at 4.9 angstrom resolution. The comprises a homo-hexadecamer IN with tetramer-of-tetramers architecture featuring eight structurally distinct types protomers supporting two catalytically competent subunits. conserved intasomal core, previously observed in simpler retroviral...
Although second-generation HIV integrase strand-transfer inhibitors (INSTIs) are prescribed throughout the world, mechanistic basis for superiority of these drugs is poorly understood. We used single-particle cryo-electron microscopy to visualize mode action advanced INSTIs dolutegravir and bictegravir at near-atomic resolution. Glutamine-148→histidine (Q148H) glycine-140→serine (G140S) amino acid substitutions in that result clinical INSTI failure perturb optimal magnesium ion coordination...
Retroviral integration favors weakly conserved palindrome sequences at the sites of viral DNA joining and generates a short (4–6 bp) duplication host flanking provirus. We previously determined two key parameters that underlie target preference for prototype foamy virus (PFV) human immunodeficiency type 1 (HIV-1) integration: flexible pyrimidine (Y)/purine (R) dinucleotide steps centers sites, base contacts with specific integrase residues, such as Ala188 in PFV Ser119 HIV-1 integrase. Here...
A multimer of retroviral integrase (IN) synapses viral DNA ends within a stable intasome nucleoprotein complex for integration into host cell genome. Reconstitution the from maedi-visna virus (MVV), an ovine lentivirus, revealed large assembly containing sixteen IN subunits1. Herein, we report cryo-EM structures lentiviral prior to engagement target and following strand transfer, refined at 3.4 3.5 Å resolution, respectively. The elucidate details protein-protein protein-DNA interfaces...
Abstract Integration into host target DNA (tDNA), a hallmark of retroviral replication, is mediated by the intasome, multimer integrase (IN) assembled on viral (vDNA) ends. To ascertain aspects tDNA recognition during integration, we have solved 3.5 Å resolution cryo-EM structure mouse mammary tumor virus (MMTV) strand transfer complex (STC) intasome. The adopts an A-like conformation in region encompassing sites vDNA joining, which exposes sugar-phosphate backbone for IN-mediated transfer....
Influenza virus genome encapsidation is essential for the formation of a helical viral ribonucleoprotein (vRNP) complex composed nucleoproteins (NP), trimeric polymerase, and genome. Although low-resolution vRNP structures are available, it remains unclear how RNA encapsidated NPs assemble into filament specific influenza vRNPs. In this study, we established biological tool, RNP-like particles assembled from recombinant A NP synthetic RNA, present first subnanometric cryo–electron microscopy...
The year 2022 was marked by the mpox outbreak caused human monkeypox virus (MPXV), which is approximately 98% identical to vaccinia (VACV) at sequence level with regard proteins involved in DNA replication. We present production baculovirus-insect cell system of VACV polymerase holoenzyme, consists E9 combination its co-factor, A20-D4 heterodimer. This led 3.8 Å cryo-electron microscopy (cryo-EM) structure DNA-free form holoenzyme. model holoenzyme constructed from high-resolution structures...
Integrase is an essential retroviral enzyme, catalyzing the stable integration of reverse transcribed DNA into cellular DNA. Several aspects mechanism, including length host sequence duplication flanking integrated provirus, which can be from 4 to 6 bp, and nucleotide preferences at site integration, are thought cluster among different genera. To date only spumavirus prototype foamy virus integrase has provided diffractable crystals integrase-DNA complexes, revealing unprecedented details on...
Abstract Between 10 and 20 million people worldwide are infected with the human T-cell lymphotropic virus type 1 (HTLV-1). Despite causing life-threatening pathologies there is no therapeutic regimen for this deltaretrovirus. Here, we screened a library of integrase strand transfer inhibitor (INSTI) candidates built around several chemical scaffolds to determine their effectiveness in limiting HTLV-1 infection. Naphthyridines substituents position 6 emerged as most potent compounds against...
Influenza viruses transcribe and replicate their genome in the nucleus of infected cells, two functions that are supported by viral RNA-dependent RNA-polymerase (FluPol). FluPol displays structural flexibility related to distinct functional states, from an inactive form conformations competent for replication transcription. machinery is constituted a structurally-invariant core comprising PB1 subunit stabilized with PA PB2 domains, whereas endonuclease C-domains can pack different...
Abstract Influenza A viruses are responsible for human seasonal epidemics and severe animal pandemics with a risk of zoonotic transmission to humans. The viral segmented RNA genome is encapsidated by nucleoproteins (NP) attached the heterotrimeric polymerase, forming ribonucleoproteins (vRNPs). Flexible helical vRNPs central transcription replication. In this study, we present an advanced biological tool, antiparallel RNP-like complex, assembled from recombinant N-terminally truncated NP...
Integrase (IN) is an important therapeutic target in the search for anti-Human Immunodeficiency Virus (HIV) inhibitors. This enzyme composed of three domains and hard to crystallize its full form. First structural results on IN were obtained catalytic core domain (CCD) avian Rous Sarcoma strain Schmidt-Ruppin A (RSV-A) CCD HIV-1 IN. ribonuclease-H like motif was revealed as well a dimeric interface stabilized by two pairs α-helices (α1/α5, α5/α1). These features have been validated other...
PASTA subunits (∼70 amino acids) are specific to bacterial serine/threonine kinases and penicillin-binding proteins (PBPs) involved in the synthesis of peptidoglycan. The human pathogen Staphylococcus aureus contains a kinase, Stk1, which plays major role virulence. A recombinant His-tagged portion extracellular domain Stk1 containing three has been crystallized using zinc sulfate as crystallizing agent. crystals belonged tetragonal space group P4122, with unit-cell parameters = 68.0, b c...
Abstract A multimer of retroviral integrase (IN) synapses viral DNA ends within a stable intasome nucleoprotein complex for integration into host cell genome. Reconstitution the from maedi-visna virus (MVV), an ovine lentivirus, revealed large assembly containing sixteen IN subunits (1). Herein, we report cryo-EM structures lentiviral prior to engagement target and following strand transfer, refined at 3.4 3.5 Å resolution, respectively. The elucidate details protein-protein protein-DNA...
ABSTRACT Retroviral intasomes are complexes assembled from purified integrase (IN) and oligonucleotides mimicking viral DNA ends (vDNA). Recombinant faithfully recapitulate integration of vDNA into a target DNA. Structural studies retroviral have revealed an array IN oligomer forms, which appear to share conserved intasome core coordinating the for strand transfer Here we explored biochemical dynamic properties mouse mammary tumor virus (MMTV) octameric intasome. We show that MMTV is...