Exploring the potential of structure-based deep learning approaches for T cell receptor design.

Deep learning methods, trained on the increasing set of available protein 3D structures and sequences, have substantially impacted the protein modeling and design field. These advancements have facilitated the creation of novel proteins, or the optimization of existing ones designed for specific functions, such as binding a target protein. Despite the demonstrated potential of such approaches in designing general protein binders, their application in designing immunotherapeutics remains relatively underexplored.

Structural characterization and AlphaFold modeling of human T cell receptor recognition of NRAS cancer neoantigens.

T cell receptors (TCRs) that recognize cancer neoantigens are important for anti-cancer immune responses and immunotherapy. Understanding the structural basis of TCR recognition of neoantigens provides insights into their exquisite specificity and can enable design of optimized TCRs. We determined crystal structures of a human TCR in complex with NRAS Q61K and Q61R neoantigen peptides and HLA-A1 MHC, revealing the molecular underpinnings for dual recognition and specificity versus wild-type NRAS peptide.

Proscan: a structure-based proline design web server.

The ability to control protein conformations and dynamics through structure-based design has been useful in various scenarios, including engineering of viral antigens for vaccines. One effective design strategy is the substitution of residues to proline amino acids, which due to its unique cyclic side chain can favor and rigidify key backbone conformations. To provide the community with a means to readily identify and explore proline designs for target proteins of interest, we developed the Proscan web server.

Exploring the Potential of Structure-Based Deep Learning Approaches for T cell Receptor Design.

Deep learning methods, trained on the increasing set of available protein 3D structures and sequences, have substantially impacted the protein modeling and design field. These advancements have facilitated the creation of novel proteins, or the optimization of existing ones designed for specific functions, such as binding a target protein. Despite the demonstrated potential of such approaches in designing general protein binders, their application in designing immunotherapeutics remains relatively unexplored.

KVFinder-web: a web-based application for detecting and characterizing biomolecular cavities.

Molecular interactions that modulate catalytic processes occur mainly in cavities throughout the molecular surface. Such interactions occur with specific small molecules due to geometric and physicochemical complementarity with the receptor. In this scenario, we present KVFinder-web, an open-source web-based application of parKVFinder software for cavity detection and characterization of biomolecular structures.

TCRmodel2: high-resolution modeling of TÂ cell receptor recognition using deep learning.

The cellular immune system, which is a critical component of human immunity, uses T cell receptors (TCRs) to recognize antigenic proteins in the form of peptides presented by major histocompatibility complex (MHC) proteins. Accurate definition of the structural basis of TCRs and their engagement of peptide-MHCs can provide major insights into normal and aberrant immunity, and can help guide the design of vaccines and immunotherapeutics. Given the limited amount of experimentally determined TCR-peptide-MHC structures and the vast amount of TCRs within each individual as well as antigenic targets, accurate computational modeling approaches are needed.

Extracellular matrix stiffness regulates degradation of MST2 via SCF .

The Hippo pathway plays central roles in relaying mechanical signals during development and tumorigenesis, but how the proteostasis of the Hippo kinase MST2 is regulated remains unknown. Here, we found that chemical inhibition of proteasomal proteolysis resulted in increased levels of MST2 in human breast epithelial cells. MST2 binds SCF E3 ubiquitin ligase and silencing βTrCP resulted in MST2 accumulation.

Structural dynamics of SARS-CoV-2 nucleocapsid protein induced by RNA binding.

The nucleocapsid (N) protein of the SARS-CoV-2 virus, the causal agent of COVID-19, is a multifunction phosphoprotein that plays critical roles in the virus life cycle, including transcription and packaging of the viral RNA. To play such diverse roles, the N protein has two globular RNA-binding modules, the N- (NTD) and C-terminal (CTD) domains, which are connected by an intrinsically disordered region. Despite the wealth of structural data available for the isolated NTD and CTD, how these domains are arranged in the full-length protein and how the oligomerization of N influences its RNA-binding activity remains largely unclear.

Structural analysis of TrkA mutations in patients with congenital insensitivity to pain reveals PLCγ as an analgesic drug target.

Chronic pain is a major health issue, and the search for new analgesics has become increasingly important because of the addictive properties and unwanted side effects of opioids. To explore potentially new drug targets, we investigated mutations in the gene found in individuals with congenital insensitivity to pain with anhidrosis (CIPA). encodes tropomyosin receptor kinase A (TrkA), the receptor for nerve growth factor (NGF) and that contributes to nociception.

pyKVFinder: an efficient and integrable Python package for biomolecular cavity detection and characterization in data science.

Background: Biomolecular interactions that modulate biological processes occur mainly in cavities throughout the surface of biomolecular structures. In the data science era, structural biology has benefited from the increasing availability of biostructural data due to advances in structural determination and computational methods. In this scenario, data-intensive cavity analysis demands efficient scripting routines built on easily manipulated data structures.

Cryo-EM structure of the mature and infective Mayaro virus at 4.4 Å resolution reveals features of arthritogenic alphaviruses.

Mayaro virus (MAYV) is an emerging arbovirus of the Americas that may cause a debilitating arthritogenic disease. The biology of MAYV is not fully understood and largely inferred from related arthritogenic alphaviruses. Here, we present the structure of MAYV at 4.

GQ-130, a novel analogue of thiazolidinedione, improves obesity-induced metabolic alterations in rats: Evidence for the involvement of PPARβ/δ pathway.

The present investigation aimed to characterize the effect of a short-time treatment with a new thiazolidinedione (TZD) derivative, GQ-130, on metabolic alterations in rats fed a high-fat diet (HFD). We investigated whether metabolic alterations induced by GQ-130 were mediated though a mechanism that involves PPARβ/δ transactivation. Potential binding and transactivation of PPARα, PPARβ/δ or PPARγ by GQ-130 were examined through cell transactivation, 8-anilino-1-naphthalenesulfonic acid (ANS) fluorescence quenching assays and thermal shift assay.

Endothelium-dependent and endothelium-independent effects of 1-nitro-2-propylbenzene on rat aorta.

A group of nitro compounds contains a benzene ring in a short aliphatic chain with the NO group, property that supposedly favors its vasodilator profile. In this study, we evaluated in isolated rat aorta the effects of 1-nitro-2-propylbenzene (NPB), a nitro compound containing the NO in the aromatic ring. In aorta precontracted with KCl, NPB (1-3000 μm) induced full endothelium-independent relaxation.

SN-38, the active metabolite of irinotecan, inhibits the acute inflammatory response by targeting toll-like receptor 4.

Purpose: Anticancer-drug efficacy seems to involve the direct interaction with host immune cells. Although topoisomerase I (Top I) inhibitors have been suggested to block LPS-evoked inflammation, the interaction between these drugs and toll-like receptor 4 (TLR4) is unaddressed.

Methods: SN-38, the active metabolite of the Top I inhibitor irinotecan, and TLR4 interaction was assessed using the in vitro luciferase nuclear factor-κB reporter assay, neutrophil migration to murine air-pouch, in silico simulation, and the thermal shift assay (TSA).

Protein Disulfide Isomerase Modulates the Activation of Thyroid Hormone Receptors.

Thyroid hormone receptors (TRs) are responsible for mediating thyroid hormone (T3 and T4) actions at a cellular level. They belong to the nuclear receptor (NR) superfamily and execute their main functions inside the cell nuclei as hormone-regulated transcription factors. These receptors also exhibit so-called "non-classic" actions, for which other cellular proteins, apart from coregulators inside nuclei, regulate their activity.

Helping students to understand physiological aspects of regional distribution of ventilation in humans: a experience from the electrical impedance tomography.

Undergraduate biomedical students often have difficulties in understanding basic concepts of respiratory physiology, particularly respiratory mechanics. In this study, we report the use of electrical impedance tomography (EIT) to improve and consolidate the knowledge about physiological aspects of normal regional distribution of ventilation in humans. Initially, we assessed the previous knowledge of a group of medical students ( n = 39) about regional differences in lung ventilation.

Vasodilator effects and putative guanylyl cyclase stimulation by 2-nitro-1-phenylethanone and 2-nitro-2-phenyl-propane-1,3-diol on rat aorta.

Compounds containing a nitro group may reveal vasodilator properties. Several nitro compounds have a NO group in a short aliphatic chain connected to an aromatic group. In this study, we evaluated in rat aorta the effects of two nitro compounds, with emphasis on a putative recruitment of the soluble guanylate cyclase (sGC) pathway to induce vasodilation.

Screening for PPAR Non-Agonist Ligands Followed by Characterization of a Hit, AM-879, with Additional No-Adipogenic and cdk5-Mediated Phosphorylation Inhibition Properties.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of a nuclear receptor superfamily and acts as a ligand-dependent transcription factor, playing key roles in maintenance of adipose tissue and in regulation of glucose and lipid homeostasis. This receptor is the target of thiazolidinediones, a class of antidiabetic drugs, which improve insulin sensitization and regulate glycemia in type 2 diabetes. Despite the beneficial effects of drugs, such as rosiglitazone and pioglitazone, their use is associated with several side effects, including weight gain, heart failure, and liver disease, since these drugs induce full activation of the receptor.

Biphasic cardiovascular and respiratory effects induced by β-citronellol.

β-Citronellol is a monoterpene found in the essential oil of various plants with antihypertensive properties. In fact, β-citronellol possesses hypotensive actions due to its vasodilator abilities. Here we aimed to show that β-citronellol recruits airway sensory neural circuitry to evoke cardiorespiratory effects.

Antispasmodic and myorelaxant effects of the flavoring agent methyl cinnamate in gut: potential inhibition of tyrosine kinase.

Methyl cinnamate (MC) is a safe flavoring agent useful to food industry. Although chemically analog to tyrosine kinase inhibitors, there is little information regarding its biological actions. Here, we aimed at assessing the MC effects on gastrointestinal contractility and the putative involvement of tyrosine kinase in the mediation of these effects.