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| Open AccessEvolutionary action and structural basis of the allosteric switch controlling β2AR functional selectivity
Ligand-induced biased signaling is thought to result in part from ligand-specific receptor conformations that cause the engagement of distinct effectors. Here the authors trace and evaluate the impact of mutations of the β2–adrenergic receptor on multiple signaling outputs to provide structural-level insight into the determinants of GPCR functional selectivity.
- Anne-Marie Schönegge
- , Jonathan Gallion
- & Michel Bouvier
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| Open AccessNanopore electric snapshots of an RNA tertiary folding pathway
While RNA folding is critical for its function, study of this process is challenging. Here, the authors combine nanopore single-molecule manipulation with theoretical analysis to follow the folding of an RNA pseudoknot, monitoring the intermediate states and the kinetics of their interconversion.
- Xinyue Zhang
- , Dong Zhang
- & Li-Qun Gu
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Article
| Open AccessSlow conformational exchange and overall rocking motion in ubiquitin protein crystals
X-ray crystallography is the main method for protein structure determination. Here the authors combine solid-state NMR measurements and molecular dynamics simulations and show that crystal packing alters the thermodynamics and kinetics of local conformational exchange as well as overall rocking motion of protein molecules in the crystal lattice.
- Vilius Kurauskas
- , Sergei A. Izmailov
- & Paul Schanda
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Article
| Open AccessPhysical properties of the HIV-1 capsid from all-atom molecular dynamics simulations
The large and complex HIV-1 capsid modulates several molecular events during HIV-1’s infective cycle. Here the authors use all-atom molecular dynamic simulations to probe the biophysical properties of the genome-free HIV-1 capsid.
- Juan R. Perilla
- & Klaus Schulten
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Article
| Open AccessAn evolutionary switch in ND2 enables Src kinase regulation of NMDA receptors
N-methyl D-aspartate receptor (NMDAR) activity is modulated by Src tyrosine kinase via the mitochondrial protein NADH dehydrogenase subunit 2 (ND2). Here the authors show that ND2 interacts with the transmembrane region of NMDAR GluN1 subunit, a process that is crucial for Src regulation of NMDAR activity.
- David P. Scanlon
- , Alaji Bah
- & Michael W. Salter
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Article
| Open AccessDefined chromosome structure in the genome-reduced bacterium Mycoplasma pneumoniae
The three-dimensional architecture of genome-reduced bacteria is poorly understood. Here the authors combine Hi-C with super-resolution microscopy inMycoplasma pneumoniaeand provide evidence of how supercoiling and local organization influences gene regulation.
- Marie Trussart
- , Eva Yus
- & Luís Serrano
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Article
| Open AccessStructural basis of ligand interaction with atypical chemokine receptor 3
The atypical chemokine receptor 3 (ACKR3) is important for cell migration in development and cancer. Here the authors combine radiolytic footprinting, disulfide trapping, mutagenesis and molecular modelling to characterize the ligand interactions and ligand-induced conformational changes in ACKR3.
- Martin Gustavsson
- , Liwen Wang
- & Tracy M. Handel
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Article
| Open AccessKCNE1 induces fenestration in the Kv7.1/KCNE1 channel complex that allows for highly specific pharmacological targeting
Specificity of inhibitors of voltage-gated ion channels is crucial for their use as therapeutics. Here, the authors show that adamantane derivatives interact with a specific binding site on fenestrations that only become available when accessory subunits are bound to the channel.
- Eva Wrobel
- , Ina Rothenberg
- & Guiscard Seebohm
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Article
| Open AccessA broadly neutralizing anti-influenza antibody reveals ongoing capacity of haemagglutinin-specific memory B cells to evolve
A major goal of vaccine design is to protect against a broad range of pathogen strains. Here the authors isolate a new broadly neutralizing antibody against influenza haemagglutinin from human memory B cells, and identify mutations that increase and broaden the neutralization towards H5 HA subtype.
- Ying Fu
- , Zhen Zhang
- & Wayne A. Marasco
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Article
| Open AccessPrediction and validation of protein intermediate states from structurally rich ensembles and coarse-grained simulations
Protein conformational changes are key to a wide range of cellular functions but remain difficult to access experimentally. Here the authors describe eBDIMS, a novel approach to predict intermediates observed in structural transition pathways from experimental ensembles.
- Laura Orellana
- , Ozge Yoluk
- & Erik Lindahl
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Article
| Open AccessThe molecular architecture of the Dam1 kinetochore complex is defined by cross-linking based structural modelling
The Dam1 complex binds kinetochores to microtubules during mitosis. Here the authors combine cross-linking/mass spectrometry with structural modelling to derive a structure for the Dam1 complex that changes when bound to microtubules; further, they provide a mechanism for regulation by Aurora B kinase.
- Alex Zelter
- , Massimiliano Bonomi
- & Trisha N. Davis
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Article
| Open AccessProtein conformational plasticity and complex ligand-binding kinetics explored by atomistic simulations and Markov models
Conformational plasticity influences several aspects of protein function. Here the authors combine extensive MD simulations with Markov state models—using trypsin as model—to reveal new mechanistic details of how conformational plasticity influence ligand-receptors interactions.
- Nuria Plattner
- & Frank Noé
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Article
| Open AccessStructural optimization of 3D-printed synthetic spider webs for high strength
Spider webs have some intriguing mechanical properties, but understanding of the properties is limited to individual silk fibres. Here, the authors create mimics of spider web using 3D techniques, which enables them to acquire knowledge of mechanical strength of the entire synthetic web.
- Zhao Qin
- , Brett G. Compton
- & Markus J. Buehler
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Activation pathway of Src kinase reveals intermediate states as targets for drug design
Activation of c-src kinase is associated with uncontrolled growth and metastasis of tumour cells. Shukla et al.model conformational changes in c-src during activation, and identify an allosteric site in an intermediate state that may provide a target for small molecule therapeutics.
- Diwakar Shukla
- , Yilin Meng
- & Vijay S. Pande
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A mitochondria-targeted inhibitor of cytochrome c peroxidase mitigates radiation-induced death
Radiomitigating compounds could be used to protect against ionizing radiation. In this study, mitochondria-targeted oleic and stearic acid derivatives are shown to inhibit pro-apoptotic oxidative events, prevent cell death, and protect mice against lethal doses of radiation.
- Jeffrey Atkinson
- , Alexandr A. Kapralov
- & Valerian E. Kagan
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Article
| Open AccessNovel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase
The influenza virus life cycle relies on sialidases, which are classified as group-1 or group-2, depending on the flexibility of the '150-loop'. In this study, chemical compounds are developed, which lock open the '150-loop', selectively inhibiting the activity of group-1 sialidases.
- Santosh Rudrawar
- , Jeffrey C. Dyason
- & Mark von Itzstein
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Article
| Open AccessStructural bases for the interaction of frataxin with the central components of iron–sulphur cluster assembly
Frataxin is an essential protein that has been linked to iron–sulphur cluster assembly, and reduced levels are associated with Friedrich's ataxia. In this study, a combination of techniques is used to probe the interactions of the bacterial frataxin orthologue CyaY with the iron–sulphur cluster assembly machinery.
- Filippo Prischi
- , Petr V. Konarev
- & Annalisa Pastore