Structural basis for CCR6 modulation by allosteric antagonists.

The CC chemokine receptor 6 (CCR6) is a potential target for chronic inflammatory diseases. Previously, we reported an active CCR6 structure in complex with its cognate chemokine CCL20, revealing the molecular basis of CCR6 activation. Here, we present two inactive CCR6 structures in ternary complexes with different allosteric antagonists, CCR6/SQA1/OXM1 and CCR6/SQA1/OXM2.

An operational workflow for producing periodic estimates of species occupancy at national scales.

Policy makers require high-level summaries of biodiversity change. However, deriving such summaries from raw biodiversity data is a complex process involving several intermediary stages. In this paper, we describe an operational workflow for generating annual estimates of species occupancy at national scales from raw species occurrence data, which can be used to construct a range of policy-relevant biodiversity indicators.

Madagascar's extraordinary biodiversity: Threats and opportunities.

Madagascar's unique biota is heavily affected by human activity and is under intense threat. Here, we review the current state of knowledge on the conservation status of Madagascar's terrestrial and freshwater biodiversity by presenting data and analyses on documented and predicted species-level conservation statuses, the most prevalent and relevant threats, ex situ collections and programs, and the coverage and comprehensiveness of protected areas. The existing terrestrial protected area network in Madagascar covers 10.

The epidemiology of head injuries at 2019 Rugby Union World Cup.

Introduction: The sequelae of concussion are of growing concern within Rugby. World Rugby has introduced rule changes to improve player welfare and reduce head injury frequency. We aimed to report the incidence of head injuries and head injury assessment (HIA) at the 2019 Rugby World Cup (RWC).

Open access journals are as likely to be referenced by the Orthopaedic literature, despite having a lower impact factor than subscription-based journals.

Background: The internet has changed the way we access and publish Orthopaedic literature. Traditional subscription journals have been challenged by the open access method of publication which permits the author to make their article available to all readers for free, often at a cost to the author. This has also been adopted in part by traditional subscription journals forming hybrid journals.

From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer's disease.

Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects.

Loss of functional diversity through anthropogenic extinctions of island birds is not offset by biotic invasions.

Human impacts reshape ecological communities through the extinction and introduction of species. The combined impact of these factors depends on whether non-native species fill the functional roles of extinct species, thus buffering the loss of functional diversity. This question has been difficult to address, because comprehensive information about past extinctions and their traits is generally lacking.

Imaging in metatarsalgia.

Metatarsalgia is a common clinical conundrum that requires careful assessment. There are a variety of causes and understanding these can help manage the pain. These causes have different imaging characteristics and require specific imaging.

Metatarsalgia: anatomy, pathology and management.

Metatarsalgia is a common presentation, particularly in middle-aged women. This review discusses the anatomical basis and classifies the different pathologies into primary, secondary and iatrogenic. The key elements to differentiate the pathologies within each classification which could cause a patient to suffer with metatarsalgia are outlined.

Crystal Structure and Subsequent Ligand Design of a Nonriboside Partial Agonist Bound to the Adenosine A Receptor.

In this study, we determined the crystal structure of an engineered human adenosine A receptor bound to a partial agonist and compared it to structures cocrystallized with either a full agonist or an antagonist/inverse agonist. The interaction between the partial agonist, belonging to a class of dicyanopyridines, and amino acids in the ligand binding pocket inspired us to develop a small library of derivatives and assess their affinity in radioligand binding studies and potency and intrinsic activity in a functional, label-free, intact cell assay. It appeared that some of the derivatives retained the partial agonist profile, whereas other ligands turned into inverse agonists.

Advances in long-wavelength native phasing at X-ray free-electron lasers.

Long-wavelength pulses from the Swiss X-ray free-electron laser (XFEL) have been used for protein structure determination by native single-wavelength anomalous diffraction (native-SAD) phasing of serial femtosecond crystallography (SFX) data. In this work, sensitive anomalous data-quality indicators and model proteins were used to quantify improvements in native-SAD at XFELs such as utilization of longer wavelengths, careful experimental geometry optimization, and better post-refinement and partiality correction. Compared with studies using shorter wavelengths at other XFELs and older software versions, up to one order of magnitude reduction in the required number of indexed images for native-SAD was achieved, hence lowering sample consumption and beam-time requirements significantly.

Clinical Outcome of Transtendon Repair of Partial Articular Supraspinatus Tendon Avulsion Tear.

Partial articular supraspinatus tendon avulsion (PASTA) tears are common. However, there is no consensus on the optimal surgical technique for the management of grade 3 tears (>50%). The authors report a retrospective consecutive case series of 64 patients with grade 3 PASTA lesions.

X-Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A Adenosine Receptor Antagonists.

We present a robust protocol based on iterations of free energy perturbation (FEP) calculations, chemical synthesis, biophysical mapping and X-ray crystallography to reveal the binding mode of an antagonist series to the A adenosine receptor (AR). Eight A AR binding site mutations from biophysical mapping experiments were initially analyzed with sidechain FEP simulations, performed on alternate binding modes. The results distinctively supported one binding mode, which was subsequently used to design new chromone derivatives.

Comparison of Orexin 1 and Orexin 2 Ligand Binding Modes Using X-ray Crystallography and Computational Analysis.

The orexin system, which consists of the two G protein-coupled receptors OX and OX, activated by the neuropeptides OX-A and OX-B, is firmly established as a key regulator of behavioral arousal, sleep, and wakefulness and has been an area of intense research effort over the past two decades. X-ray structures of the receptors in complex with 10 new antagonist ligands from diverse chemotypes are presented, which complement the existing structural information for the system and highlight the critical importance of lipophilic hotspots and water molecules for these peptidergic GPCR targets. Learnings from the structural information regarding the utility of pharmacophore models and how selectivity between OX and OX can be achieved are discussed.

Identification of a novel allosteric GLP-1R antagonist HTL26119 using structure- based drug design.

A series of novel allosteric antagonists of the GLP-1 receptor (GLP-1R), exemplified by HTL26119, are described. SBDD approaches were employed to identify HTL26119, exploiting structural understanding of the allosteric binding site of the closely related Glucagon receptor (GCGR) (Jazayeri et al., 2016) and the homology relationships between GCGR and GLP-1R.

Projected losses of global mammal and bird ecological strategies.

Species, and their ecological strategies, are disappearing. Here we use species traits to quantify the current and projected future ecological strategy diversity for 15,484 land mammals and birds. We reveal an ecological strategy surface, structured by life-history (fast-slow) and body mass (small-large) as one major axis, and diet (invertivore-herbivore) and habitat breadth (generalist-specialist) as the other.

Improving generation length estimates for the IUCN Red List.

The International Union for the Conservation of Nature (IUCN) Red List classifies species according to their risk of extinction, informing local to global conservation decisions. Here we look to advance the estimation of generation length, which is used as a time-scalar in the Red List as a way of accounting for differences in species' life-histories. We calculated or predicted generation length for 86 species of antelope following the Rspan approach.

Agonists and Antagonists of Protease-Activated Receptor 2 Discovered within a DNA-Encoded Chemical Library Using Mutational Stabilization of the Target.

The discovery of ligands via affinity-mediated selection of DNA-encoded chemical libraries is driven by the quality and concentration of the protein target. G-protein-coupled receptors (GPCRs) and other membrane-bound targets can be difficult to isolate in their functional state and at high concentrations, and therefore have been challenging for affinity-mediated selection. Here, we report a successful selection campaign against protease-activated receptor 2 (PAR2).

Towards high throughput GPCR crystallography: In Meso soaking of Adenosine A Receptor crystals.

Here we report an efficient method to generate multiple co-structures of the A G protein-coupled receptor (GPCR) with small-molecules from a single preparation of a thermostabilised receptor crystallised in Lipidic Cubic Phase (LCP). Receptor crystallisation is achieved following purification using a low affinity "carrier" ligand (theophylline) and crystals are then soaked in solutions containing the desired (higher affinity) compounds. Complete datasets to high resolution can then be collected from single crystals and seven structures are reported here of which three are novel.

Impact of protein-ligand solvation and desolvation on transition state thermodynamic properties of adenosine A ligand binding kinetics.

Ligand-protein binding kinetic rates are growing in importance as parameters to consider in drug discovery and lead optimization. In this study we analysed using surface plasmon resonance (SPR) the transition state (TS) properties of a set of six adenosine A receptor inhibitors, belonging to both the xanthine and the triazolo-triazine scaffolds. SPR highlighted interesting differences among the ligands in the enthalpic and entropic components of the TS energy barriers for the binding and unbinding events.

Structure of the complement C5a receptor bound to the extra-helical antagonist NDT9513727.

The complement system is a crucial component of the host response to infection and tissue damage. Activation of the complement cascade generates anaphylatoxins including C5a and C3a. C5a exerts a pro-inflammatory effect via the G-protein-coupled receptor C5a anaphylatoxin chemotactic receptor 1 (C5aR1, also known as CD88) that is expressed on cells of myeloid origin.

Structural Mapping of Adenosine Receptor Mutations: Ligand Binding and Signaling Mechanisms.

The four adenosine receptors (ARs), A, A, A, and A, constitute a subfamily of G protein-coupled receptors (GPCRs) with exceptional foundations for structure-based ligand design. The vast amount of mutagenesis data, accumulated in the literature since the 1990s, has been recently supplemented with structural information, currently consisting of several inactive and active structures of the A and inactive conformations of the A ARs. We provide the first integrated view of the pharmacological, biochemical, and structural data available for this receptor family, by mapping onto the relevant crystal structures all site-directed mutagenesis data, curated and deposited at the GPCR database (available through http://www.

Serial millisecond crystallography for routine room-temperature structure determination at synchrotrons.

Historically, room-temperature structure determination was succeeded by cryo-crystallography to mitigate radiation damage. Here, we demonstrate that serial millisecond crystallography at a synchrotron beamline equipped with high-viscosity injector and high frame-rate detector allows typical crystallographic experiments to be performed at room-temperature. Using a crystal scanning approach, we determine the high-resolution structure of the radiation sensitive molybdenum storage protein, demonstrate soaking of the drug colchicine into tubulin and native sulfur phasing of the human G protein-coupled adenosine receptor.