Sea Anemone Kunitz Peptide HCIQ2c1: Structure, Modulation of TRPA1 Channel, and Suppression of Nociceptive Reaction In Vivo.

TRPA1 is a homotetrameric non-selective calcium-permeable channel. It contributes to chemical and temperature sensitivity, acute pain sensation, and development of inflammation. HCIQ2c1 is a peptide from the sea anemone that inhibits serine proteases.

Structure-based prediction of T cell receptor recognition of unseen epitopes using TCRen.

T cell receptor (TCR) recognition of foreign peptides presented by major histocompatibility complex protein is a major event in triggering the adaptive immune response to pathogens or cancer. The prediction of TCR-peptide interactions has great importance for therapy of cancer as well as infectious and autoimmune diseases but remains a major challenge, particularly for novel (unseen) peptide epitopes. Here we present TCRen, a structure-based method for ranking candidate unseen epitopes for a given TCR.

[B vitamins and diseases of the peripheral nervous system].

Various diseases of the peripheral nervous system are associated with metabolic disorders of B vitamins. A lack of neurotropic vitamins, which began in the early stages of the development of a bacterial disease, led to its more rapid development. The article analyzes data on B vitamin deficiency in the pathogenesis of the most dangerous diseases of the peripheral nervous system.

The scorpion toxin BeKm-1 blocks hERG cardiac potassium channels using an indispensable arginine residue.

BeKm-1 is a peptide toxin from scorpion venom that blocks the pore of the potassium channel hERG (K11.1) in the human heart. Although individual protein structures have been resolved, the structure of the complex between hERG and BeKm-1 is unknown.

Molecular Basis for Mambalgin-2 Interaction with Heterotrimeric α-ENaC/ASIC1a/γ-ENaC Channels in Cancer Cells.

Cancer progression is characterized by microenvironmental acidification. Tumor cells adapt to low environmental pH by activating acid-sensing trimeric ion channels of the DEG/ENaC family. The α-ENaC/ASIC1a/γ-ENaC heterotrimeric channel is a tumor-specific acid-sensing channel, and its targeting can be considered a new strategy for cancer therapy.

[Digital health: elderly use of electronic services.].

Since the first decade of the XXI century the digitalization of the healthcare system in Russia has been actively carried out according to interrelated federal and regional projects. The older generation has well-established habits and prefers traditional channels for obtaining information and services - by phone and during a personal visit, and moreover, they are even afraid to use electronic services. The vulnerability of the elderly was especially exacerbated during the CODID-19 pandemic and after, when strict restrictive measures on freedom of movement were introduced and many services began to be provided remotely.

Fighting Celiac Disease: Improvement of pH Stability of Cathepsin L In Vitro by Computational Design.

Roughly 1% of the global population is susceptible to celiac disease (CD)-inheritable autoimmune inflammation of the small intestine caused by intolerance to gliadin proteins present in wheat, rye, and barley grains, and called gluten in wheat. Classical treatment is a life-long gluten-free diet, which is constraining and costly. An alternative approach is based upon the development and oral reception of effective peptidases that degrade in the stomach immunogenic proline- and glutamine-rich gliadin peptides, which are the cause of the severe reaction in the intestine.

Specific Binding of the α-Component of the Lantibiotic Lichenicidin to the Peptidoglycan Precursor Lipid II Predetermines Its Antimicrobial Activity.

To date, a number of lantibiotics have been shown to use lipid II-a highly conserved peptidoglycan precursor in the cytoplasmic membrane of bacteria-as their molecular target. The α-component (Lchα) of the two-component lantibiotic lichenicidin, previously isolated from the VK21 strain, seems to contain two putative lipid II binding sites in its -terminal and -terminal domains. Using NMR spectroscopy in DPC micelles, we obtained convincing evidence that the -terminal mersacidin-like site is involved in the interaction with lipid II.

Orientational Preferences of GPI-Anchored Ly6/uPAR Proteins.

Ly6/uPAR proteins regulate many essential functions in the nervous and immune systems and epithelium. Most of these proteins contain single β-structural LU domains with three protruding loops and are glycosylphosphatidylinositol (GPI)-anchored to a membrane. The GPI-anchor role is currently poorly studied.

Neurological Signs of Postcovid Syndrome.

The challenge of postcovid syndrome (PCS) is of great interest due to its wide distribution and variety of clinical signs. The main neurological signs of PCS are discussed. Data on the presumptive mechanisms forming PCS are presented.

The Mechanism of Selective Recognition of Lipid Substrate by hDHHC20 Enzyme.

S-acylation is a post-translational linkage of long chain fatty acids to cysteines, playing a key role in normal physiology and disease. In human cells, the reaction is catalyzed by a family of 23 membrane DHHC-acyltransferases (carrying an Asp-His-His-Cys catalytic motif) in two stages: (1) acyl-CoA-mediated autoacylation of the enzyme; and (2) further transfer of the acyl chain to a protein substrate. Despite the availability of a 3D-structure of human acyltransferase (hDHHC20), the molecular aspects of lipid selectivity of DHHC-acyltransferases remain unclear.

Membrane-mediated interaction of non-conventional snake three-finger toxins with nicotinic acetylcholine receptors.

Nicotinic acetylcholine receptor of α7 type (α7-nAChR) presented in the nervous and immune systems and epithelium is a promising therapeutic target for cognitive disfunctions and cancer treatment. Weak toxin from Naja kaouthia venom (WTX) is a non-conventional three-finger neurotoxin, targeting α7-nAChR with weak affinity. There are no data on interaction mode of non-conventional neurotoxins with nAChRs.

Molecular Dynamics of DHHC20 Acyltransferase Suggests Principles of Lipid and Protein Substrate Selectivity.

Lipid modification of viral proteins with fatty acids of different lengths (S-acylation) is crucial for virus pathogenesis. The reaction is catalyzed by members of the DHHC family and proceeds in two steps: the autoacylation is followed by the acyl chain transfer onto protein substrates. The crystal structure of human DHHC20 (hDHHC20), an enzyme involved in the acylation of S-protein of SARS-CoV-2, revealed that the acyl chain may be inserted into a hydrophobic cavity formed by four transmembrane (TM) α-helices.

[Neurological manifestations of postcovid syndrome].

The problem of postcovid syndrome (PCS) attracts great interest due to the wide prevalence and variety of clinical manifestations. The main neurological manifestations of PCS are considered. The information about the proposed mechanisms of the formation of PCS is given.

Molecular Dynamics Insight into the Lipid II Recognition by Type A Lantibiotics: Nisin, Epidermin, and Gallidermin.

Lanthionine-containing peptides (lantibiotics) have been considered as pharmaceutical candidates for decades, although their clinical application has been restricted. Most lantibiotics kill bacteria targeting and segregating of the cell wall precursor-membrane-inserted lipid II molecule-in some cases accompanied by pores formation. Nisin-like lantibiotics specifically bind to pyrophosphate (PPi) moiety of lipid II with their structurally similar N-terminal thioether rings A and B.

Conserved Structure and Evolution of DPF Domain of PHF10-The Specific Subunit of PBAF Chromatin Remodeling Complex.

Transcription activation factors and multisubunit coactivator complexes get recruited at specific chromatin sites via protein domains that recognize histone modifications. Single PHDs (plant homeodomains) interact with differentially modified H3 histone tails. Double PHD finger (DPF) domains possess a unique structure different from PHD and are found in six proteins: histone acetyltransferases MOZ and MORF; chromatin remodeling complex BAF (DPF1-3); and chromatin remodeling complex PBAF (PHF10).

Human Three-Finger Protein Lypd6 Is a Negative Modulator of the Cholinergic System in the Brain.

Lypd6 is a GPI-tethered protein from the Ly-6/uPAR family expressed in the brain. Lypd6 enhances the Wnt/β-catenin signaling, although its action on nicotinic acetylcholine receptors (nAChRs) have been also proposed. To investigate a cholinergic activity of Lypd6, we studied a recombinant water-soluble variant of the human protein (ws-Lypd6) containing isolated "three-finger" LU-domain.

Potassium channel blocker crafted by α-hairpinin scaffold engineering.

The α-Hairpinins are a family of plant defense peptides with a common fold presenting two short α-helices stabilized by two invariant S-S-bridges. We have shown previously that substitution of just two amino acid residues in a wheat α-hairpinin Tk-AMP-X2 leads to Tk-hefu-2 that features specific affinity to voltage-gated potassium channels K1.3.

Tuning Scorpion Toxin Selectivity: Switching From K1.1 to K1.3.

Voltage-gated potassium channels (Ks) perform vital physiological functions and are targets in different disorders ranging from ataxia and arrhythmia to autoimmune diseases. An important issue is the search for and production of selective ligands of these channels. Peptide toxins found in scorpion venom named KTx excel in both potency and selectivity with respect to some potassium channel isoforms, which may present only minute differences in their structure.

Environmental and dynamic effects explain how nisin captures membrane-bound lipid II.

Antibiotics (AB) resistance is a major threat to global health, thus the development of novel AB classes is urgently needed. Lantibiotics (i.e.

Thermodynamically Consistent Equation of State for an Accreted Neutron Star Crust.

We study the equation of state (EOS) of an accreting neutron star crust. Usually, such an EOS is obtained by assuming (implicitly) that the free (unbound) neutrons and nuclei in the inner crust move together. We argue that this assumption violates the condition μ_{n}^{∞}=const, required for hydrostatic (and diffusion) equilibrium of unbound neutrons (μ_{n}^{∞} is the redshifted neutron chemical potential).

Probing temperature and capsaicin-induced activation of TRPV1 channel via computationally guided point mutations in its pore and TRP domains.

In a recent computational study, we revealed some mechanistic aspects of TRPV1 (transient receptor potential channel 1) thermal activation and gating and proposed a set of probable functionally important residues - "hot spots" that have not been characterized experimentally yet. In this work, we analyzed TRPV1 point mutants G643A, I679A + A680G, and K688G/P combining molecular modeling, biochemistry, and electrophysiology. The substitution G643A reduced maximal conductivity that resulted in a normal response to moderate stimuli, but a relatively weak response to more intensive activation.

Impact of external amino acids on fluorescent protein chromophore biosynthesis revealed by molecular dynamics and mutagenesis studies.

The precise positioning of catalytic amino acids against the substrate in an enzyme active site is a crucial factor in biocatalysis. Biosynthesis of the chromophores of fluorescent proteins (FPs) is an autocatalytic process that must conform to these requirements. Here, we show that, in addition to the internal amino acid residues in the proximity of the chromophore, chromophore biosynthesis is influenced by the remote amino acids exposed on the outer surface of the β-barrel structure of the FP.