@TOME 3.0: Interfacing Protein Structure Modeling and Ligand Docking.

Knowledge of protein-ligand complexes is essential for efficient drug design. Virtual docking can bring important information on putative complexes but it is still far from being simultaneously fast and accurate. Receptors are flexible and adapt to the incoming small molecules while docking is highly sensitive to small conformational deviations.

The structural landscape and diversity of Pyricularia oryzae MAX effectors revisited.

Magnaporthe AVRs and ToxB-like (MAX) effectors constitute a family of secreted virulence proteins in the fungus Pyricularia oryzae (syn. Magnaporthe oryzae), which causes blast disease on numerous cereals and grasses. In spite of high sequence divergence, MAX effectors share a common fold characterized by a ß-sandwich core stabilized by a conserved disulfide bond.

Adaptive evolution in virulence effectors of the rice blast fungus Pyricularia oryzae.

Plant pathogens secrete proteins called effectors that target host cellular processes to promote disease. Recently, structural genomics has identified several families of fungal effectors that share a similar three-dimensional structure despite remarkably variable amino-acid sequences and surface properties. To explore the selective forces that underlie the sequence variability of structurally-analogous effectors, we focused on MAX effectors, a structural family of effectors that are major determinants of virulence in the rice blast fungus Pyricularia oryzae.

SecretoMyc, a web-based database on mycobacteria secreted proteins and structure-based homology identification using bio-informatics tools.

To better understand the interaction between the host and the Mycobacterium tuberculosis pathogen, it is critical to identify its potential secreted proteins. While various experimental methods have been successful in identifying proteins under specific culture conditions, they have not provided a comprehensive characterisation of the secreted proteome. We utilized a combination of bioinformatics servers and in-house software to identify all potentially secreted proteins from six mycobacterial genomes through the three secretion systems: SEC, TAT, and T7SS.

A Mycobacterium tuberculosis Effector Targets Mitochondrion, Controls Energy Metabolism, and Limits Cytochrome Exit.

Host metabolism reprogramming is a key feature of Mycobacterium tuberculosis () infection that enables the survival of this pathogen within phagocytic cells and modulates the immune response facilitating the spread of the tuberculosis disease. Here, we demonstrate that a previously uncharacterized secreted protein from , Rv1813c, manipulates the host metabolism by targeting mitochondria. When expressed in eukaryotic cells, the protein is delivered to the mitochondrial intermembrane space and promotes the enhancement of host ATP production by boosting the oxidative phosphorylation metabolic pathway.

A new family of structurally conserved fungal effectors displays epistatic interactions with plant resistance proteins.

Recognition of a pathogen avirulence (AVR) effector protein by a cognate plant resistance (R) protein triggers a set of immune responses that render the plant resistant. Pathogens can escape this so-called Effector-Triggered Immunity (ETI) by different mechanisms including the deletion or loss-of-function mutation of the AVR gene, the incorporation of point mutations that allow recognition to be evaded while maintaining virulence function, and the acquisition of new effectors that suppress AVR recognition. The Dothideomycete Leptosphaeria maculans, causal agent of oilseed rape stem canker, is one of the few fungal pathogens where suppression of ETI by an AVR effector has been demonstrated.

Programmable receptors enable bacterial biosensors to detect pathological biomarkers in clinical samples.

Bacterial biosensors, or bactosensors, are promising agents for medical and environmental diagnostics. However, the lack of scalable frameworks to systematically program ligand detection limits their applications. Here we show how novel, clinically relevant sensing modalities can be introduced into bactosensors in a modular fashion.

Resolving the activation mechanism of the D99N antiterminator LicT protein.

LicT is an antiterminator protein of the BglG family whose members are key players in the control of carbohydrate catabolism in bacteria. These antiterminators are generally composed of three modules, an N-terminal RNA-binding domain (CAT) followed by two homologous regulation modules (PRD1 and PRD2) that control the RNA binding activity of the effector domain via phosphorylation on conserved histidines. Although several structures of isolated domains of BglG-like proteins have been described, no structure containing CAT and at least one PRD simultaneously has yet been reported in an active state, precluding detailed understanding of signal transduction between modules.

Structural Insights into of the Allosteric Activation of the LicT Antiterminator by PTS-Mediated Phosphorylation.

LicT belongs to an essential family of bacterial transcriptional antitermination proteins controlling the expression of sugar-metabolizing operons. When activated, they bind to nascent mRNAs, preventing premature arrest of transcription. The RNA binding capacity of the N-terminal domain CAT is controlled by phosphorylations of two homologous regulation modules by the phosphotransferase system (PTS).

Comprehensive classification of the plant non-specific lipid transfer protein superfamily towards its sequence-structure-function analysis.

Background: Non-specific Lipid Transfer Proteins (nsLTPs) are widely distributed in the plant kingdom and constitute a superfamily of related proteins. Several hundreds of different nsLTP sequences-and counting-have been characterized so far, but their biological functions remain unclear. It has been clear for years that they present a certain interest for agronomic and nutritional issues.

KNOTTIN: the database of inhibitor cystine knot scaffold after 10 years, toward a systematic structure modeling.

Knottins, or inhibitor cystine knots (ICKs), are ultra-stable miniproteins with multiple applications in drug design and medical imaging. These widespread and functionally diverse proteins are characterized by the presence of three interwoven disulfide bridges in their structure, which form a unique pseudoknot. Since 2004, the KNOTTIN database (www.

Recognition of the Effector AVR-Pia by the Decoy Domain of the Rice NLR Immune Receptor RGA5.

Nucleotide binding domain and leucine-rich repeat proteins (NLRs) are important receptors in plant immunity that allow recognition of pathogen effectors. The rice () NLR RGA5 recognizes the effector AVR-Pia through direct interaction. Here, we gained detailed insights into the molecular and structural bases of AVR-Pia-RGA5 interaction and the role of the RATX1 decoy domain of RGA5.

Structure Analysis Uncovers a Highly Diverse but Structurally Conserved Effector Family in Phytopathogenic Fungi.

Phytopathogenic ascomycete fungi possess huge effector repertoires that are dominated by hundreds of sequence-unrelated small secreted proteins. The molecular function of these effectors and the evolutionary mechanisms that generate this tremendous number of singleton genes are largely unknown. To get a deeper understanding of fungal effectors, we determined by NMR spectroscopy the 3-dimensional structures of the Magnaporthe oryzae effectors AVR1-CO39 and AVR-Pia.

Structure and modeling of knottins, a promising molecular scaffold for drug discovery.

The knottins are extremely stable miniproteins present in many species and are able to perform various tasks. Owing to its small size and its amazing stability, the knottin structural domain is considered as an excellent scaffold for drug development. Several recent databases and web servers dedicated to or aware of knottins have appeared and are shortly described.

Optimizing structural modeling for a specific protein scaffold: knottins or inhibitor cystine knots.

Background: Knottins are small, diverse and stable proteins with important drug design potential. They can be classified in 30 families which cover a wide range of sequences (1621 sequenced), three-dimensional structures (155 solved) and functions (> 10). Inter knottin similarity lies mainly between 15% and 40% sequence identity and 1.

Knottin cyclization: impact on structure and dynamics.

Background: Present in various species, the knottins (also referred to as inhibitor cystine knots) constitute a group of extremely stable miniproteins with a plethora of biological activities. Owing to their small size and their high stability, knottins are considered as excellent leads or scaffolds in drug design. Two knottin families contain macrocyclic compounds, namely the cyclotides and the squash inhibitors.

Structure and folding of disulfide-rich miniproteins: insights from molecular dynamics simulations and MM-PBSA free energy calculations.

The fold of small disulfide-rich proteins largely relies on two or more disulfide bridges that are main components of the hydrophobic core. Because of the small size of these proteins and their high cystine content, the cysteine connectivity has been difficult to ascertain in some cases, leading to uncertainties and debates in the literature. Here, we use molecular dynamics simulations and MM-PBSA free energy calculations to compare similar folds with different disulfide pairings in two disulfide-rich miniprotein families, namely the knottins and the short-chain scorpion toxins, for which the connectivity has been discussed.

KNOTTIN: the knottin or inhibitor cystine knot scaffold in 2007.

The KNOTTIN database provides standardized information on the small disulfide-rich proteins with a knotted topology called knottins or inhibitor cystine knots. Static pages present the essential historical or recent results about knottin discoveries, sequences, structures, syntheses, folding, functions, applications and bibliography. New tools, KNOTER3D and KNOTER1D, are provided to determine or predict if a user query (3D structure or sequence) is a knottin.

PAT: a protein analysis toolkit for integrated biocomputing on the web.

PAT, for Protein Analysis Toolkit, is an integrated biocomputing server. The main goal of its design was to facilitate the combination of different processing tools for complex protein analyses and to simplify the automation of repetitive tasks. The PAT server provides a standardized web interface to a wide range of protein analysis tools.

EvDTree: structure-dependent substitution profiles based on decision tree classification of 3D environments.

Background: Structure-dependent substitution matrices increase the accuracy of sequence alignments when the 3D structure of one sequence is known, and are successful e.g. in fold recognition.

Squash inhibitors: from structural motifs to macrocyclic knottins.

In this article, we will first introduce the squash inhibitor, a well established family of highly potent canonical serine proteinase inhibitors isolated from Cucurbitaceae. The squash inhibitors were among the first discovered proteins with the typical knottin fold shared by numerous peptides extracted from plants, animals and fungi. Knottins contain three knotted disulfide bridges, two of them arranged as a Cystine-Stabilized Beta-sheet motif.

The KNOTTIN website and database: a new information system dedicated to the knottin scaffold.

The KNOTTIN website and database organize information about knottins or inhibitor cystine knots, small disulfide-rich proteins with a knotted topology. Thanks to their small size and high stability, knottins provide appealing scaffolds for protein engineering and drug design. Static pages present the main historical and recent results about knottin discoveries, sequences, structures, folding, functions, applications and bibliography.