New insight into the tick neuronal nicotinic acetylcholine receptors: from molecular to pharmacological studies.

ACh is known to be an excitatory neurotransmitter in the central nervous system of several arthropod species. Nicotinic acetylcholine receptors are involved in rapid neurotransmission and are the target of compounds used as acaricides. In the present review, we discuss recent data on the study of the functional properties of tick neuronal nicotinic acetylcholine receptor subtypes present in the synganglion.

Aquaporin Modulation by Cations, a Review.

Aquaporins (AQPs) are transmembrane channels initially discovered for their role in water flux facilitation through biological membranes. Over the years, a much more complex and subtle picture of these channels appeared, highlighting many other solutes accommodated by AQPs and a dense regulatory network finely tuning cell membranes' water permeability. At the intersection between several transduction pathways (e.

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

Inherited cardiomyopathies are 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 β-cardiac myosin, the molecular motor driving heart contraction. Omecamtiv mecarbil and Mavacamten are two such molecules that completed phase 3 clinical trials, and the inhibitor Mavacamten is now approved by the FDA.

Deciphering Molecular Mechanisms Involved in the Modulation of Human Aquaporins' Water Permeability by Zinc Cations: A Molecular Dynamics Approach.

Aquaporins (AQPs) constitute a wide family of water channels implicated in all kind of physiological processes. Zinc is the second most abundant trace element in the human body and a few studies have highlighted regulation of AQP0 and AQP4 by zinc. In the present work, we addressed the putative regulation of AQPs by zinc cations in silico through molecular dynamics simulations of human AQP0, AQP2, AQP4, and AQP5.

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 β-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 and the inhibitor .

Stimulation of ATP Hydrolysis by ssDNA Provides the Necessary Mechanochemical Energy for G4 Unfolding.

The G-quadruplex (G4) is a distinct geometric and electrophysical structure compared to classical double-stranded DNA, and its stability can impede essential cellular processes such as replication, transcription, and translation. This study focuses on the BsPif1 helicase, revealing its ability to bind independently to both single-stranded DNA (ssDNA) and G4 structures. The unfolding activity of BsPif1 on G4 relies on the presence of a single tail chain, and the covalent continuity between the single tail chain and the G4's main chain is necessary for efficient G4 unwinding.

pharmacological study of AQP2 inhibition by steroids contextualized to Ménière's disease treatments.

Ménière's disease (MD) is characterized by an abnormal dilatation of the endolymphatic compartment called endolymphatic hydrops and is associated with fluctuating hearing losses and vertigo. Corticosteroid treatment is typically administered for its anti-inflammatory effects to MD patients. However, we recently described for the first time a direct interaction of two corticosteroids (dexamethasone and cortisol) with human AQP2 which strongly inhibited water fluxes.

Plant Aquaporin Gating Is Reversed by Phosphorylation on Intracellular Loop D-Evidence from Molecular Dynamics Simulations.

Aquaporins (AQPs) constitute a wide and ancient protein family of transmembrane channels dedicated to the regulation of water exchange across biological membranes. In plants, higher numbers of AQP homologues have been conserved compared to other kingdoms of life such as in animals or in bacteria. As an illustration of this plant-specific functional diversity, plasma membrane intrinsic proteins (PIPs, i.

Mechanism of small molecule inhibition of Plasmodium falciparum myosin A informs antimalarial drug design.

Malaria results in more than 500,000 deaths per year and the causative Plasmodium parasites continue to develop resistance to all known agents, including different antimalarial combinations. The class XIV myosin motor PfMyoA is part of a core macromolecular complex called the glideosome, essential for Plasmodium parasite mobility and therefore an attractive drug target. Here, we characterize the interaction of a small molecule (KNX-002) with PfMyoA.

Cryo-EM structure of the folded-back state of human β-cardiac myosin.

To save energy and precisely regulate cardiac contractility, cardiac muscle myosin heads are sequestered in an 'off' state that can be converted to an 'on' state when exertion is increased. The 'off' state is equated with a folded-back structure known as the interacting-heads motif (IHM), which is a regulatory feature of all class-2 muscle and non-muscle myosins. We report here the human β-cardiac myosin IHM structure determined by cryo-electron microscopy to 3.

Cryo-EM structure of the folded-back state of human β-cardiac myosin.

During normal levels of exertion, many cardiac muscle myosin heads are sequestered in an off-state even during systolic contraction to save energy and for precise regulation. They can be converted to an on-state when exertion is increased. Hypercontractility caused by hypertrophic cardiomyopathy (HCM) myosin mutations is often the result of shifting the equilibrium toward more heads in the on-state.

Cortisol Interaction with Aquaporin-2 Modulates Its Water Permeability: Perspectives for Non-Genomic Effects of Corticosteroids.

Aquaporins (AQPs) are water channels widely distributed in living organisms and involved in many pathophysiologies as well as in cell volume regulations (CVR). In the present study, based on the structural homology existing between mineralocorticoid receptors (MRs), glucocorticoid receptors (GRs), cholesterol consensus motif (CCM) and the extra-cellular vestibules of AQPs, we investigated the binding of corticosteroids on the AQP family through in silico molecular dynamics simulations of AQP2 interactions with cortisol. We propose, for the first time, a putative AQPs corticosteroid binding site (ACBS) and discussed its conservation through structural alignment.

A Perspective for Ménière's Disease: In Silico Investigations of Dexamethasone as a Direct Modulator of AQP2.

Ménière's 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.

Noncanonical Function of AGO2 Augments T-cell Receptor Signaling in T-cell Prolymphocytic Leukemia.

Unlabelled: T-cell prolymphocytic leukemia (T-PLL) is a chemotherapy-refractory T-cell malignancy with limited therapeutic options and a poor prognosis. Current disease concepts implicate TCL1A oncogene-mediated enhanced T-cell receptor (TCR) signaling and aberrant DNA repair as central perturbed pathways. We discovered that recurrent gains on chromosome 8q more frequently involve the argonaute RISC catalytic component 2 (AGO2) gene than the adjacent MYC locus as the affected minimally amplified genomic region.

Crystal structures of N-terminally truncated telomerase reverse transcriptase from fungi‡.

Telomerase plays critical roles in cellular aging, in the emergence and/or development of cancer, and in the capacity for stem-cell renewal, consists of a catalytic telomerase reverse transcriptase (TERT) and a template-encoding RNA (TER). TERs from diverse organisms contain two conserved structural elements: the template-pseudoknot (T-PK) and a helical three-way junction (TWJ). Species-specific features of the structure and function of telomerase make obtaining a more in-depth understanding of the molecular mechanism of telomerase particularly important.

The actomyosin interface contains an evolutionary conserved core and an ancillary interface involved in specificity.

Plasmodium falciparum, the causative agent of malaria, moves by an atypical process called gliding motility. Actomyosin interactions are central to gliding motility. However, the details of these interactions remained elusive until now.

Fungal -Intrinsic Protein Aquaporin from : Structural and Functional Considerations.

The major intrinsic protein (MIP) superfamily is a key part of the fungal transmembrane transport network. It facilitates the transport of water and low molecular weight solutes across biomembranes. The fungal uncharacterized X-Intrinsic Protein (XIP) subfamily includes the full protein diversity of MIP.

Full-length myosin A and essential light chain PfELC structures provide new anti-malarial targets.

Parasites from the genus Plasmodium are the causative agents of malaria. The mobility, infectivity, and ultimately pathogenesis of rely on a macromolecular complex, called the glideosome. At the core of the glideosome is an essential and divergent Myosin A motor (PfMyoA), a first order drug target against malaria.

Voltage-gating of aquaporins, a putative conserved safety mechanism during ionic stresses.

Aquaporins are transmembrane water channels found in almost every living organism. Numerous studies have brought a good understanding of both water transport through their pores and the regulations taking place at the molecular level, but subtleties remain to be clarified. Recently, a voltage-related gating mechanism involving the conserved arginine of the channel's main constriction was captured for human aquaporins through molecular dynamics studies.

Plasmodium myosin A drives parasite invasion by an atypical force generating mechanism.

Plasmodium parasites are obligate intracellular protozoa and causative agents of malaria, responsible for half a million deaths each year. The lifecycle progression of the parasite is reliant on cell motility, a process driven by myosin A, an unconventional single-headed class XIV molecular motor. Here we demonstrate that myosin A from Plasmodium falciparum (PfMyoA) is critical for red blood cell invasion.

Characterization of LuWRKY36, a flax transcription factor promoting secoisolariciresinol biosynthesis in response to Fusarium oxysporum elicitors in Linum usitatissimum L. hairy roots.

The involvement of a WRKY transcription factor in the regulation of lignan biosynthesis in flax using a hairy root system is described. Secoisolariciresinol is the main flax lignan synthesized by action of LuPLR1 (pinoresinol-lariciresinol reductase 1). LuPLR1 gene promoter deletion experiments have revealed a promoter region containing W boxes potentially responsible for the response to Fusarium oxysporum.

The control exerted by ABA on lignan biosynthesis in flax (Linum usitatissimum L.) is modulated by a Ca signal transduction involving the calmodulin-like LuCML15b.

The LuPLR1 gene encodes a pinoresinol lariciresinol reductase responsible for the biosynthesis of (+)-secoisolariciresinol, a cancer chemopreventive lignan, highly accumulated in the seedcoat of flax (Linum usitatissimum L.). Abscisic acid (ABA) plays a key role in the regulation of LuPLR1 gene expression and lignan accumulation in both seeds and cell suspensions, which require two cis-acting elements (ABRE and MYB2) for this regulation.

Pinoresinol-lariciresinol reductases, key to the lignan synthesis in plants.

This paper provides an overview on activity, stereospecificity, expression and regulation of pinoresinol-lariciresinol reductases in plants. These enzymes are shared by the pathways to all 8-8' lignans derived from pinoresinol. Pinoresinol-lariciresinol reductases (PLR) are enzymes involved in the lignan biosynthesis after the initial dimerization of two monolignols.

Hypertrophic cardiomyopathy disease results from disparate impairments of cardiac myosin function and auto-inhibition.

Hypertrophic cardiomyopathies (HCM) result from distinct single-point mutations in sarcomeric proteins that lead to muscle hypercontractility. While different models account for a pathological increase in the power output, clear understanding of the molecular basis of dysfunction in HCM is the mandatory next step to improve current treatments. Here, we present an optimized quasi-atomic model of the sequestered state of cardiac myosin coupled to X-ray crystallography and in silico analysis of the mechanical compliance of the lever arm, allowing the systematic study of a large set of HCM mutations and the definition of different mutation classes based on their effects on lever arm compliance, sequestered state stability, and motor functions.