How Do Gepotidacin and Zoliflodacin Stabilize DNA-Cleavage Complexes with Bacterial Type IIA Topoisomerases? 2. A Single Moving Metal Mechanism.

DNA gyrase is a bacterial type IIA topoisomerase that can create temporary double-stranded DNA breaks to regulate DNA topology and an archetypical target of antibiotics. The widely used quinolone class of drugs use a water-metal ion bridge in interacting with the GyrA subunit of DNA gyrase. Zoliflodacin sits in the same pocket as quinolones but interacts with the GyrB subunit and also stabilizes lethal double-stranded DNA breaks.

How Do Gepotidacin and Zoliflodacin Stabilize DNA Cleavage Complexes with Bacterial Type IIA Topoisomerases? 1. Experimental Definition of Metal Binding Sites.

One of the challenges for experimental structural biology in the 21st century is to see chemical reactions happen. () DNA gyrase is a type IIA topoisomerase that can create temporary double-stranded DNA breaks to regulate DNA topology. Drugs, such as gepotidacin, zoliflodacin and the quinolone moxifloxacin, can stabilize these normally transient DNA strand breaks and kill bacteria.

Hydrodynamic insights into the paleobiology of the Ediacaran rangeomorph .

The Ediacaran of Newfoundland preserves some of the oldest complex macroscopic communities, several of which are dominated by the fractal-like rangeomorph genus . Here we use computational fluid dynamics and a detailed reconstruction of to document for the first time hydrodynamic phenomena associated with this sediment-reclining organism and its rangeomorph elements that are relevant to interpreting feeding strategies, explain the recently documented rheotropic growth oblique to currents, and provide insights into their impact on the Ediacaran seafloor. Obliquely oriented are common, likely representing a compromise between maximized aspect ratio and minimization of drag.

Outcomes of the EMDataResource cryo-EM Ligand Modeling Challenge.

The EMDataResource Ligand Model Challenge aimed to assess the reliability and reproducibility of modeling ligands bound to protein and protein-nucleic acid complexes in cryogenic electron microscopy (cryo-EM) maps determined at near-atomic (1.9-2.5 Å) resolution.

Earth's sinking surface.

China's major cities show considerable subsidence from human activities.

Disappearing cities on US coasts.

The sea level along the US coastlines is projected to rise by 0.25-0.3 m by 2050, increasing the probability of more destructive flooding and inundation in major cities.

Outcomes of the EMDataResource Cryo-EM Ligand Modeling Challenge.

The EMDataResource Ligand Model Challenge aimed to assess the reliability and reproducibility of modeling ligands bound to protein and protein/nucleic-acid complexes in cryogenic electron microscopy (cryo-EM) maps determined at near-atomic (1.9-2.5 Å) resolution.

Current trends in macromolecular model refinement and validation.

The Guest Editors provide an introduction to the special issue of articles based on talks at the CCP4 Study Weekend 2022, which is available at https://journals.iucr.org/special_issues/2023/CCP42022/.

Neutron crystallographic refinement with REFMAC5 from the CCP4 suite.

Hydrogen (H) atoms are abundant in macromolecules and often play critical roles in enzyme catalysis, ligand-recognition processes and protein-protein interactions. However, their direct visualization by diffraction techniques is challenging. Macromolecular X-ray crystallography affords the localization of only the most ordered H atoms at (sub-)atomic resolution (around 1.

Exploratory modelling of the impacts of sea-level rise on the Sundarbans mangrove forest, West Bengal, India.

In this paper we conduct exploratory simulations of the possible evolution of the Indian Sundarbans mangroves to 2100 under a range of future sea-level rise (SLR) scenarios, considering the effects of both inundation and shoreline erosion. The Sea Level Affecting Marshes Model (SLAMM) is used to simulate habitat transitions due to inundation and these outputs are combined with an empirical model of SLR-driven shoreline erosion. A set of plausible climate-induced SLR scenarios are considered, together with delta subsidence and constrained vertical sediment accretion.

The CCP4 suite: integrative software for macromolecular crystallography.

The Collaborative Computational Project No. 4 (CCP4) is a UK-led international collective with a mission to develop, test, distribute and promote software for macromolecular crystallography. The CCP4 suite is a multiplatform collection of programs brought together by familiar execution routines, a set of common libraries and graphical interfaces.

GEMMI and Servalcat restrain REFMAC5.

Macromolecular refinement uses experimental data together with prior chemical knowledge (usually digested into geometrical restraints) to optimally fit an atomic structural model into experimental data, while ensuring that the model is chemically plausible. In the CCP4 suite this chemical knowledge is stored in a Monomer Library, which comprises a set of restraint dictionaries. To use restraints in refinement, the model is analysed and template restraints from the dictionary are used to infer (i) restraints between concrete atoms and (ii) the positions of riding hydrogen atoms.

Insulin secretion deficits in a Prader-Willi syndrome β-cell model are associated with a concerted downregulation of multiple endoplasmic reticulum chaperones.

Prader-Willi syndrome (PWS) is a multisystem disorder with neurobehavioral, metabolic, and hormonal phenotypes, caused by loss of expression of a paternally-expressed imprinted gene cluster. Prior evidence from a PWS mouse model identified abnormal pancreatic islet development with retention of aged insulin and deficient insulin secretion. To determine the collective roles of PWS genes in β-cell biology, we used genome-editing to generate isogenic, clonal INS-1 insulinoma lines having 3.

Global survey shows planners use widely varying sea-level rise projections for coastal adaptation.

Including sea-level rise (SLR) projections in planning and implementing coastal adaptation is crucial. Here we analyze the first global survey on the use of SLR projections for 2050 and 2100. Two-hundred and fifty-three coastal practitioners engaged in adaptation/planning from 49 countries provided complete answers to the survey which was distributed in nine languages - Arabic, Chinese, English, French, Hebrew, Japanese, Korean, Portuguese and Spanish.

Benefits of subsidence control for coastal flooding in China.

Land subsidence is impacting large populations in coastal Asia via relative sea-level rise (RSLR). Here we assesses these risks and possible response strategies for China, including estimates of present rates of RSLR, flood exposure and risk to 2050. In 2015, each Chinese coastal resident experienced on average RSLR of 11 to 20 mm/yr.

CCP4 Cloud for structure determination and project management in macromolecular crystallography.

Nowadays, progress in the determination of three-dimensional macromolecular structures from diffraction images is achieved partly at the cost of increasing data volumes. This is due to the deployment of modern high-speed, high-resolution detectors, the increased complexity and variety of crystallographic software, the use of extensive databases and high-performance computing. This limits what can be accomplished with personal, offline, computing equipment in terms of both productivity and maintainability.

Targeting climate adaptation to safeguard and advance the Sustainable Development Goals.

The international community has committed to achieve 169 Sustainable Development Goal (SDG) targets by 2030 and to enhance climate adaptation under the Paris Agreement. Despite the potential for synergies, aligning SDG and climate adaptation efforts is inhibited by an inadequate understanding of the complex relationship between SDG targets and adaptation to impacts of climate change. Here we propose a framework to conceptualise how ecosystems and socio-economic sectors mediate this relationship, which provides a more nuanced understanding of the impacts of climate change on all 169 SDG targets.

Tyrosine 121 moves revealing a ligandable pocket that couples catalysis to ATP-binding in serine racemase.

Human serine racemase (hSR) catalyses racemisation of L-serine to D-serine, the latter of which is a co-agonist of the NMDA subtype of glutamate receptors that are important in synaptic plasticity, learning and memory. In a 'closed' hSR structure containing the allosteric activator ATP, the inhibitor malonate is enclosed between the large and small domains while ATP is distal to the active site, residing at the dimer interface with the Tyr121 hydroxyl group contacting the α-phosphate of ATP. In contrast, in 'open' hSR structures, Tyr121 sits in the core of the small domain with its hydroxyl contacting the key catalytic residue Ser84.

Updated restraint dictionaries for carbohydrates in the pyranose form.

Restraint dictionaries are used during macromolecular structure refinement to encapsulate intramolecular connectivity and geometric information. These dictionaries allow previously determined `ideal' values of features such as bond lengths, angles and torsions to be used as restraint targets. During refinement, restraints influence the model to adopt a conformation that agrees with prior observation.

Sustainability of the coastal zone of the Ganges-Brahmaputra-Meghna delta under climatic and anthropogenic stresses.

The Ganges-Brahmaputra-Meghna (GBM) delta is one of the world's largest deltas. It is currently experiencing high rates of relative sea-level rise of about 5 mm/year, reflecting anthropogenic climate change and land subsidence. This is expected to accelerate further through the 21st Century, so there are concerns that the GBM delta will be progressively submerged.

Developing socio-ecological scenarios: A participatory process for engaging stakeholders.

Deltas are experiencing profound demographic, economic and land use changes and human-induced catchment and climate change. Bangladesh exemplifies these difficulties through multiple climate risks including subsidence/sea-level rise, temperature rise, and changing precipitation patterns, as well as changing management of the Ganges and Brahmaputra catchments. There is a growing population and economy driving numerous more local changes, while dense rural population and poverty remain significant.

Towards Consistency in Geometry Restraints for Carbohydrates in the Pyranose form: Modern Dictionary Generators Reviewed.

Macromolecular restrained refinement is nowadays the most used method for improving the agreement between an atomic structural model and experimental data. Restraint dictionaries, a key tool behind the success of the method, allow fine-tuning geometric properties such as distances and angles between atoms beyond simplistic expectations. Dictionary generators can provide restraint target estimates derived from different sources, from fully theoretical to experimental and any combination in between.

Twenty-first-century projections of shoreline change along inlet-interrupted coastlines.

Sandy coastlines adjacent to tidal inlets are highly dynamic and widespread landforms, where large changes are expected due to climatic and anthropogenic influences. To adequately assess these important changes, both oceanic (e.g.

The missing link: covalent linkages in structural models.

Covalent linkages between constituent blocks of macromolecules and ligands have been subject to inconsistent treatment during the model-building, refinement and deposition process. This may stem from a number of sources, including difficulties with initially detecting the covalent linkage, identifying the correct chemistry, obtaining an appropriate restraint dictionary and ensuring its correct application. The analysis presented herein assesses the extent of problems involving covalent linkages in the Protein Data Bank (PDB).