Biology subjects

Rety, S.

Publications and source records attributed to Rety, S..

4 recordsLinked to original sources

bioRxiv2023

Omecamtiv mecarbil and Mavacamten target the same myosin pocket despite antagonistic effects in heart contraction

Inherited cardiomyopathies are amongst the most common cardiac diseases worldwide, leading in the late-stage to heart failure and death. The most promising treatments against these diseases are small-molecules directly modulating the force produced by {beta}-cardiac myosin, the molecular motor driving heart contraction. Two of these molecules that produce antagonistic effects on cardiac contractility have completed clinical phase 3 trials: the activator Omecamtiv mecarbil and the inhibitor Mavacamten. In this work, we reveal by X-ray crystallography that both drugs target the same pocket and stabilize a pre-stroke structural state, with only few local differences. All atoms molecular dynamics simulations reveal how these molecules can have antagonistic impact on the allostery of the motor by comparing {beta}-cardiac myosin in the apo form or bound to Omecamtiv mecarbil or Mavacamten. Altogether, our results provide the framework for rational drug development for the purpose of personalized medicine.

molecular biology↗

bioRxiv2023

HTLV-1 Rex hijacks UPF1 in a CRM1 dependent manner, leading to NMD inhibition and revealing unexpected proviral roles of UPF1

The hijacking of CRM1 export is an important step of the retroviral replication cycle. Here, we investigated the consequences of this hijacking for the host. During HTLV-1 infection, we identified that this hijacking by the viral protein Rex favours the association between CRM1 and the RNA helicase UPF1, leading to a decreased affinity of UPF1 for cellular RNA and its nuclear retention. As a consequence, we found that the nonsense mediated mRNA decay (NMD), known to have an antiviral function, was inhibited. Corroborating these results, we described a similar process with Rev, the functional homolog of Rex from HIV-1. Unexpectedly, we also found that, for HTLV-1, this process is coupled with the specific loading of UPF1 onto vRNA, independently of NMD. In this latter context, UPF1 positively regulates several steps of the viral replication cycle, from the nuclear export of vRNA to the production of mature viral particles. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/545693v2_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1e91e61org.highwire.dtl.DTLVardef@1c9951borg.highwire.dtl.DTLVardef@15c6021org.highwire.dtl.DTLVardef@1ab35ff_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO During retroviral replication, the nuclear export unspliced vRNA is conducted via the hijacking of the exportin CRM1 by the viral protein Rex. In parallel, the RNA helicase UPF1 is naturally exported in a CRM1 dependent manner. In the cytoplasm it drives NMD, whose substrates include vRNA. Here we demonstrated that HTLV-1 Rex dependent hijacking of CRM1 is associated with the nuclear accumulation of UPF1 and the stabilization of the interaction between CRM1 and UPF1 (1). In this complex, UPF1 shows a decreased affinity for cellular RNA associated to NMD inhibition (2). We also observed that UPF1 is selectively loaded onto vRNA and stimulates vRNA export (3). In this context, UPF1 is driven in the viral particles (without NMD cofactors) where it plays critical role in virion assembly, maturation (4) and ultimately viral infection (5). Created in BioRender. PROCHASSON, L. (2025) https://BioRender.com/urj0cvo". C_FIG

molecular biology↗

bioRxiv2022

Dexamethasone, a direct modulator of AQP2 in Meniere s disease.

Menieres disease is a chronic illness characterized by intermittent episodes of vertigo associated with fluctuating sensorineural hearing loss, tinnitus and aural pressure. This pathology strongly correlates with a dilatation of the fluid compartment of the endolymph, so-called hydrops. Dexamethasone is one of the therapeutic approaches recommended when conventional antivertigo treatments have failed. Several mechanisms of actions have been hypothesized for the mode of action of dexamethasone such as anti-inflammatory effect or as a regulator of the inner ear water homeostasis. However, none of them have been experimentally confirmed so far. Aquaporins (AQPs) are transmembrane water channels and are hence central in the regulation of trans-cellular water fluxes. In the present study we investigated the hypothesis that dexamethasone could impact water fluxes in the inner ear through direct interaction with AQP2. We addressed this question through molecular dynamics simulations approaches and managed to demonstrate a direct interaction between AQP2 and dexamethasone and its significant impact on the channel water permeability. We also describe the molecular mechanisms involved in dexamethasone binding and in its regulatory action upon AQP2 function. HighlightsO_LIAQP2 water permeability is modulated by dexamethasone at physiological concentrations C_LIO_LIThe interaction impacts water fluxes through a direct interaction with the extra-cellular surface of the aquaporin C_LIO_LIKey interactions implicate conserved residues of the ar/R constriction C_LIO_LINew insights on corticosteroids mode of actions in Menieres disease treatment C_LI

biochemistry↗

bioRxiv2021

Structural mechanism underpinning Thermus oshimai Pif1-mediated G-quadruplex unfolding

G-quadruplexes (G4s) are unusual DNA structures and can stall DNA replication, causing genomic instability for the cell. Although the solved crystal structure of the DHX36 helicase demonstrated that G4 was specifically targeted by a DHX36-specific motif (DSM), lack of complete structural details for general G4-resolving helicases without specific target motifs remains a barrier to the complete understanding of the molecular basis underlying the recognition and unfolding of G4s. Herein, we present the first X-ray crystal structure of the Thermus oshimai Pif1 (ToPif) complexed with a G4, thereby mimicking the physiological G4 formed during DNA replication. Strictly different from the previous determined G4-helicase structure of DHX36, our structure revealed that ToPif1 recognizes the entire native G4 via a cluster of amino acids at domains 1B/2B constituting a G4-Recognizing Surface (GRS). The overall topology of the G4 structure solved in this work maintains its three-layered propeller-type G4 topology, with no significant reorganization of G-tetrads upon protein binding. The three G-tetrads in G4 were differentially recognized by GRS residues mainly through electrostatic, ionic interactions and hydrogen bonds formed between the GRS residues and the ribose-phosphate backbone. Our structure explains how helicases from distinct superfamilies adopt different strategies for recognizing and unfolding G4s.

biophysics↗