Type II Binders Targeting the "GLR-Out" Conformation of the Pseudokinase STRADα.

Pseudokinases play important roles in signal transduction and cellular processes similar to those of catalytically competent kinases. However, pseudokinase pharmacological tractability and conformational space accessibility are poorly understood. Pseudokinases have only recently been suggested to adopt "inactive" conformations or interact with conformation-specific kinase inhibitors (e.

Identification of a G-Protein-Independent Activator of GIRK Channels.

G-protein-gated inwardly rectifying K (GIRK) channels are essential effectors of inhibitory neurotransmission in the brain. GIRK channels have been implicated in diseases with abnormal neuronal excitability, including epilepsy and addiction. GIRK channels are tetramers composed of either the same subunit (e.

Structures of ligand-occupied β-Klotho complexes reveal a molecular mechanism underlying endocrine FGF specificity and activity.

The three members of the endocrine fibroblast growth factor (FGF) family designated FGF19, FGF21, and FGF23 mediate their pleiotropic cellular effects by binding to and activating binary complexes composed of an FGF receptor (FGFR) bound to either α-Klotho or β-Klotho receptors. Structural analyses of ligand-occupied Klotho extracellular domains have provided important insights concerning mechanisms underlying the binding specificities of FGF21 and FGF23 to β-Klotho or α-Klotho, respectively. They have also demonstrated that Klotho proteins function as primary high-affinity receptors while FGFRs function as the catalytic subunits that mediate intracellular signaling.

An IRAK1-PIN1 signalling axis drives intrinsic tumour resistance to radiation therapy.

Drug-based strategies to overcome tumour resistance to radiotherapy (R-RT) remain limited by the single-agent toxicity of traditional radiosensitizers (for example, platinums) and a lack of targeted alternatives. In a screen for compounds that restore radiosensitivity in p53 mutant zebrafish while tolerated in non-irradiated wild-type animals, we identified the benzimidazole anthelmintic oxfendazole. Surprisingly, oxfendazole acts via the inhibition of IRAK1, a kinase thus far implicated in interleukin-1 receptor (IL-1R) and Toll-like receptor (TLR) immune responses.

Encounter and React: Computer-Guided Design of Covalent Inhibitors.

Covalent inhibitors can obtain optimal selectivity and extended residence time. In this issue of Cell Chemical Biology, Shraga et al. (2019) take a comprehensive computational and experimental approach to modulate the JNK-Jun pathway through design of MKK7 covalent inhibitors.

KinaMetrix: a web resource to investigate kinase conformations and inhibitor space.

Protein kinases are among the most explored protein drug targets. Visualization of kinase conformations is critical for understanding structure-function relationship in this family and for developing chemically unique, conformation-specific small molecule drugs. We have developed Kinformation, a random forest classifier that annotates the conformation of over 3500 protein kinase structures in the Protein Data Bank.

Novel selective thiadiazine DYRK1A inhibitor lead scaffold with human pancreatic β-cell proliferation activity.

The Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A) is an enzyme that has been implicated as an important drug target in various therapeutic areas, including neurological disorders (Down syndrome, Alzheimer's disease), oncology, and diabetes (pancreatic β-cell expansion). Current small molecule DYRK1A inhibitors are ATP-competitive inhibitors that bind to the kinase in an active conformation. As a result, these inhibitors are promiscuous, resulting in pharmacological side effects that limit their therapeutic applications.

Redefining the Protein Kinase Conformational Space with Machine Learning.

Protein kinases are dynamic, adopting different conformational states that are critical for their catalytic activity. We assess a range of structural features derived from the conserved αC helix and DFG motif to define the conformational space of the catalytic domain of protein kinases. We then construct Kinformation, a random forest classifier, to annotate the conformation of 3,708 kinase structures in the PDB.

GEN3VA: aggregation and analysis of gene expression signatures from related studies.

Background: Genome-wide gene expression profiling of mammalian cells is becoming a staple of many published biomedical and biological research studies. Such data is deposited into data repositories such as the Gene Expression Omnibus (GEO) for potential reuse. However, these repositories currently do not provide simple interfaces to systematically analyze collections of related studies.

SLC Transporters: Structure, Function, and Drug Discovery.

The human Solute Carrier (SLC) transporters are important targets for drug development. Structure-based drug discovery for SLC transporters requires the description of their structure, dynamics, and mechanism of interaction with small molecule ligands and ions. The recent determination of atomic structures of human SLC transporters and their homologs, combined with improved computational power and prediction methods have led to an increased applicability of structure-based drug design methods for human SLC members.

Molecular Basis for Redox Activation of Epidermal Growth Factor Receptor Kinase.

Epidermal growth factor receptor (EGFR) is a target of signal-derived H2O2, and oxidation of active-site cysteine 797 to sulfenic acid enhances kinase activity. Although a major class of covalent drugs targets C797, nothing is known about its catalytic importance or how S-sulfenylation leads to activation. Here, we report the first detailed functional analysis of C797.

Inhibitor Discovery for the Human GLUT1 from Homology Modeling and Virtual Screening.

The human Glucose Transporter 1 (hGLUT1 or SLC2A1) is a facilitative membrane transporter found in the liver, intestines, kidney, and brain, where it transports sugars such as d-glucose and d-galactose. Genetic variations in hGLUT1 are associated with a broad range of diseases and metabolic disorders. For example, hGLUT1 is upregulated in various cancer types (e.

DFGmodel: predicting protein kinase structures in inactive states for structure-based discovery of type-II inhibitors.

Protein kinases exist in equilibrium of active and inactive states, in which the aspartate-phenylalanine-glycine motif in the catalytic domain undergoes conformational changes that are required for function. Drugs targeting protein kinases typically bind the primary ATP-binding site of an active state (type-I inhibitors) or utilize an allosteric pocket adjacent to the ATP-binding site in the inactive state (type-II inhibitors). Limited crystallographic data of protein kinases in the inactive state hampers the application of rational drug discovery methods for developing type-II inhibitors.

Identification of key hinge residues important for nucleotide-dependent allostery in E. coli Hsp70/DnaK.

DnaK is a molecular chaperone that has important roles in protein folding. The hydrolysis of ATP is essential to this activity, and the effects of nucleotides on the structure and function of DnaK have been extensively studied. However, the key residues that govern the conformational motions that define the apo, ATP-bound, and ADP-bound states are not entirely clear.

CSAR benchmark exercise of 2010: combined evaluation across all submitted scoring functions.

As part of the Community Structure-Activity Resource (CSAR) center, a set of 343 high-quality, protein-ligand crystal structures were assembled with experimentally determined K(d) or K(i) information from the literature. We encouraged the community to score the crystallographic poses of the complexes by any method of their choice. The goal of the exercise was to (1) evaluate the current ability of the field to predict activity from structure and (2) investigate the properties of the complexes and methods that appear to hinder scoring.

CSAR benchmark exercise of 2010: selection of the protein-ligand complexes.

A major goal in drug design is the improvement of computational methods for docking and scoring. The Community Structure Activity Resource (CSAR) aims to collect available data from industry and academia which may be used for this purpose ( www.csardock.