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| Open AccessInhibitor-3 inhibits Protein Phosphatase 1 via a metal binding dynamic protein–protein interaction
Protein phosphatase 1 (PP1) is regulated by intrinsically disordered proteins like inhibitor-3, I3. The authors show that I3 does not inhibit PP1 by forming a rigid complex but instead by binding dynamically with its active site metals, showing how flexibility is used in biology.
- Gautam Srivastava
- , Meng S. Choy
- & Wolfgang Peti
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Article
| Open AccessThe structural basis of the pH-homeostasis mediated by the Cl−/HCO3− exchanger, AE2
Cells maintain a narrow physiological pH by exchanging intracellular bicarbonate for extracellular chloride. Here, authors determine the cryo-EM structures of human anion exchanger 2 (AE2) in five major operating states and one transitional state, to collectively demonstrate the process of pH-balancing.
- Qing Zhang
- , Liyan Jian
- & Yu Cao
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Article
| Open AccessMutation in glutamate transporter homologue GltTk provides insights into pathologic mechanism of episodic ataxia 6
Episodic ataxias (EAs) are rare neurological conditions that cause motor impairment. Here the authors investigated the molecular mechanism of such a pathological condition caused by a mutation of a conserved proline into arginine residue.
- Emanuela Colucci
- , Zaid R. Anshari
- & Albert Guskov
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Article
| Open AccessStructural insights into the mechanism of leptin receptor activation
Leptin is a master regulator of body weight and energy homeostasis that is dysregulated in obesity. Here, authors determined the cryo-EM structure of the activated Leptin receptor complex, revealing insights into the mechanism of Leptin signaling
- Robert A. Saxton
- , Nathanael A. Caveney
- & K. Christopher Garcia
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Article
| Open AccessStructural basis of the substrate recognition and inhibition mechanism of Plasmodium falciparum nucleoside transporter PfENT1
PfENT1 is a promising antimalarial drug target. Here, authors report cryo-EM structures of PfENT1 that, together with biochemical work, suggests PfENT1 is an inosine transporter and describe the inhibitory mechanism of the endofacial inhibitor, GSK4.
- Chen Wang
- , Leiye Yu
- & Dong Deng
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Article
| Open AccessSingle-molecule localization microscopy reveals the ultrastructural constitution of distal appendages in expanded mammalian centrioles
The authors have combined direct stochastic optical reconstruction microscopy with expansion microscopy to describe the 3-dimensional molecular organization of centriolar distal appendages.
- Ting-Jui Ben Chang
- , Jimmy Ching-Cheng Hsu
- & T. Tony Yang
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Article
| Open AccessStructural and functional analysis of human pannexin 2 channel
The PANX2 channel is involved in skin homeostasis and neuronal development, but the molecular basis of channel function remains largely unknown. Here, the authors provide detailed analysis of the structure, function, and pharmacology of human PANX2.
- Zhihui He
- , Yonghui Zhao
- & Peng Yuan
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Article
| Open AccessCryo-EM structure of human eIF5A-DHS complex reveals the molecular basis of hypusination-associated neurodegenerative disorders
eIF5A is the only protein known to contain hypusine. Here, the authors present the cryoEM structure of the eIF5A-DHS complex and provide mechanistic insights to understand the deoxyhypusination reaction and hypusination-related neurodegeneration.
- Elżbieta Wątor
- , Piotr Wilk
- & Przemysław Grudnik
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Article
| Open AccessStructural insights into the human niacin receptor HCA2-Gi signalling complex
Hydroxyl-carboxylic acid receptor 2 (HCA2) functions as a high-affinity receptor for nicotinic acid (vitamin B3). Here, authors report the cryo-EM structure of the HCA2-Gi complex with the agonist MK-6892 and inactive state crystal structures of mutation stabilized HCA2, to describe the mechanism of HCA2 signaling.
- Yang Yang
- , Hye Jin Kang
- & Zhi-Jie Liu
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Article
| Open AccessModulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics
AMPA receptors associated with TARP subunits enable the development of selective AMPA receptor drugs. Here, the authors provide cryo-EM structures of receptors bound to three TARP-γ8 selective drugs, and reveal bifunctionality of one ligand.
- Danyang Zhang
- , Remigijus Lape
- & Ingo H. Greger
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Article
| Open AccessTransmembrane signaling by a synthetic receptor in artificial cells
Transmembrane signaling is the core adaptation in nature that allows cells to communicate. Here, the authors engineer signaling through the lipid bilayer using chemical, synthetic receptors for their use in the design of artificial cells.
- Ane Bretschneider Søgaard
- , Andreas Bøtker Pedersen
- & Alexander N. Zelikin
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Article
| Open AccessCurvature induces active velocity waves in rotating spherical tissues
The existence of multicellular systems relies on coordinated cell motion in three dimensions. Here, cell migration in rotating spherical tissues is shown to exhibit a collective mode with a single-wavelength velocity wave, which arises from the effect of curvature on the flocking behavior of cells on a spherical surface.
- Tom Brandstätter
- , David B. Brückner
- & Chase P. Broedersz
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Article
| Open AccessFTD-tau S320F mutation stabilizes local structure and allosterically promotes amyloid motif-dependent aggregation
The authors used multi-disciplinary approaches to understand the structural mechanism underlying spontaneous aggregation of tau encoding an S320F FTD-tau mutant. Understanding the mechanisms of tau aggregation will help identify novel methods to regulate its misfolding.
- Dailu Chen
- , Sofia Bali
- & Lukasz A. Joachimiak
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Article
| Open AccessTwo gates mediate NMDA receptor activity and are under subunit-specific regulation
NMDA receptors are glutamate-gated ion channels that regulate fast signaling in the brain. Here, the authors show that the opening and closing patterns of the channel derive from the action of two gates that are regulated by distinct subunits.
- Johansen B. Amin
- , Miaomiao He
- & Lonnie P. Wollmuth
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Article
| Open AccessA myoelectric digital twin for fast and realistic modelling in deep learning
Muscle electrophysiology is a promising tool for human-machine approaches in medicine and beyond clinical applications. The authors propose here a model simulating electric signals produced during human movements and apply this data for training of deep learning algorithms.
- Kostiantyn Maksymenko
- , Alexander Kenneth Clarke
- & Dario Farina
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Article
| Open AccessInsights into receptor structure and dynamics at the surface of living cells
It is challenging to approach protein structures in living cells. Here the authors investigate Interleukin-4 receptor alpha, which has a noncanonical amino acid incorporated at different locations, and see that evaluating click efficiency with calibrated imaging gives information on structure-related properties.
- Frederik Steiert
- , Peter Schultz
- & Thomas Weidemann
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Article
| Open AccessStructural basis for TRIM72 oligomerization during membrane damage repair
TRIM72 oligomerization via intermolecular disulfide bonds is important for cells to repair damaged membranes. Here, authors report the crystal structure of TRIM72 dimer and show that TRIM72 B-box dimerization facilitates TRIM72 oligomerization.
- Yuemin Ma
- , Lei Ding
- & Chun Zhou
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Article
| Open AccessRobust automated backbone triple resonance NMR assignments of proteins using Bayesian-based simulated annealing
The authors present BARASA, an approach to assign backbone triple resonance spectra of proteins that augments traditional approaches with a Bayesian statistical analysis of the observed chemical shifts. The algorithm employs a simulated annealing engine to establish a consensus set of resonance assignments and is tested against systems ranging in size to over 450 amino acids including examples of intrinsically disordered proteins.
- Anthony C. Bishop
- , Glorisé Torres-Montalvo
- & A. Joshua Wand
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Article
| Open AccessInsights into membrane association of the SMP domain of extended synaptotagmin
The SMP domain of E-Syts is a newly identified lipid transfer module with unclear mechanisms. Here, authors show that it uses its tip region to associate with the extremely curved or negatively charged membranes to extract and unload lipids.
- Yunyun Wang
- , Zhenni Li
- & Xin Bian
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Article
| Open AccessThe architecture of transmembrane and cytoplasmic juxtamembrane regions of Toll-like receptors
Toll-like receptors (TLRs) play a key role in the innate immune system. Here, Kornilov et al. resolve the 3D structures of the membrane-associated parts of four TLRs to reveal properties of the juxta-membrane domain.
- F. D. Kornilov
- , A. V. Shabalkina
- & K. S. Mineev
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Article
| Open AccessMechanism underlying delayed rectifying in human voltage-mediated activation Eag2 channel
Human Eag2 is a voltage-gated potassium channel with unique delayed rectifying gating kinetics. Here, authors show how voltage opens the channel and illuminate a mechanism of delayed rectifier gating.
- Mingfeng Zhang
- , Yuanyue Shan
- & Duanqing Pei
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Article
| Open AccessStructural dynamics in the evolution of SARS-CoV-2 spike glycoprotein
In this paper, the authors use hydrogen-deuterium exchange mass spectrometry to describe how the SARS-CoV-2 spike glycoprotein has evolved its structural dynamics features and receptor binding capability from the emergence of the original Wuhan isolate to the recent omicron variant. The findings reported shed light on the evolution of SARS-CoV-2 in the human population and the mechanisms of emergence of new variants.
- Valeria Calvaresi
- , Antoni G. Wrobel
- & Argyris Politis
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Article
| Open AccessTRAK adaptors regulate the recruitment and activation of dynein and kinesin in mitochondrial transport
The mechanisms of microtubule-based mitochondrial transport remain poorly understood. Here, the authors show that the mitochondrial TRAK adaptors activate the dynein-dynactin complex, enhance the motility of kinesin, and can scaffold both motors to control bidirectional transport.
- John T. Canty
- , Andrew Hensley
- & Ahmet Yildiz
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Article
| Open AccessStructural basis of vitamin C recognition and transport by mammalian SVCT1 transporter
Sodium-dependent vitamin C transporters are responsible for vitamin C uptake and tissue distribution in mammals. Here, authors present cryo-EM structures of mouse SVCT1 in both the apo and substrate-bound states, revealing the structural basis of substrate recognition and transport.
- Mingxing Wang
- , Jin He
- & Ji She
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Article
| Open AccessCryo-EM structures of human Cx36/GJD2 neuronal gap junction channel
Connexin 36 (Cx36) gap junction channel is responsible for signal transmission in electrical synapses. Here, the authors determine cryo-EM structures of Cx36, providing insights into a potential role of lipids in the channel gating.
- Seu-Na Lee
- , Hwa-Jin Cho
- & Hyung Ho Lee
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Article
| Open AccessMolecular mechanism of biased signaling at the kappa opioid receptor
Biased signaling in κ-opiod receptors (KOR) offer an attractive strategy for pain management. Here the authors identify determinants of KOR signaling bias using structural methods in combination with molecular dynamics simulations.
- Amal El Daibani
- , Joseph M. Paggi
- & Tao Che
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Article
| Open AccessReal-time single-molecule 3D tracking in E. coli based on cross-entropy minimization
Single-molecule 3D tracking is critical to understand macromolecular dynamics but achieving this at a sub-millisecond resolution remains challenging. Here the authors present a 3D tracking method based on cross-entropy minimization and the true excitation point spread function.
- Elias Amselem
- , Bo Broadwater
- & Johan Elf
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Article
| Open AccessIntermediate-state-trapped mutants pinpoint G protein-coupled receptor conformational allostery
Understanding of GPCR activation is limited as the structural information fails to present the full spectrum of energy landscape. Here, authors establish a series of conformation-biased mutants that represent five conformational states lying along adenosine A2A receptor (A2AR) activation.
- Xudong Wang
- , Chris Neale
- & Libin Ye
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Article
| Open AccessPhotocrosslinking-induced CRAC channel-like Orai1 activation independent of STIM1
The Ca2+ ion channel Orai1 is crucial in immune cells. Here, the authors applied genetic code expansion to transfer light-sensitivity to the Orai1 channel and achieved precise control over its function.
- Lena Maltan
- , Sarah Weiß
- & Isabella Derler
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Article
| Open AccessTwo-step structural changes in M3 muscarinic receptor activation rely on the coupled Gq protein cycle
During Gq protein activation, the separated Gαq-GTP forms a stable complex with the ligand-activated hM3R and PLCβ. Here the authors demonstrate that a single M3 receptor FRET probe can display the real-time conformational dynamics of innate receptor by the downstream Gq protein cycle.
- Yong-Seok Kim
- , Jun-Hee Yeon
- & Byung-Chang Suh
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Article
| Open AccessStructural basis of peptide recognition and activation of endothelin receptors
Endothelin receptors (ETAR and ETBR) are critical for vasoregulation and are targets for cardiovascular diseases treatment. Here, the authors offer a structural basis for peptide recognition selectivity and activation of both endothelin receptors.
- Yujie Ji
- , Jia Duan
- & Yi Jiang
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Article
| Open AccessOptical control of PIEZO1 channels
PIEZO proteins are large, mechanically-activated trimeric ion channels. Here the authors report a light-gated mouse PIEZO1 channel, mOP1, whereby an azobenzene-based photoswitch covalently localised at the extracellular apex of a transmembrane helix, rapidly triggers channel gating on light irradiation.
- Francisco Andrés Peralta
- , Mélaine Balcon
- & Thomas Grutter
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Article
| Open AccessStructural basis of HIV-1 maturation inhibitor binding and activity
HIV maturation inhibitors such as bevirimat (BVM) interfering with Gag processing are emerging as alternative anti-retroviral drug candidates. Here, the authors report structures of assemblies of HIV-1 Gag fragments spanning the CA C-terminal domain and SP1 region bound to BVM.
- Sucharita Sarkar
- , Kaneil K. Zadrozny
- & Tatyana Polenova
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Article
| Open AccessRobust total X-ray scattering workflow to study correlated motion of proteins in crystals
X-ray diffraction images contain a signal that is an untapped source of information on protein dynamics. Here, the authors lay out a general workflow for interpreting this diffuse scattering signal and expanding the capabilities of protein crystallography.
- Steve P. Meisburger
- , David A. Case
- & Nozomi Ando
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Article
| Open AccessCryo-EM structure of human heptameric pannexin 2 channel
Pannexin 2 plays critical roles in many physiological processes but its mechanism remain unclear. Here, authors report the cryo-EM structure of human Panx2 in the open state and identify critical residues for its gating.
- Hang Zhang
- , Shiyu Wang
- & Huawei Zhang
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Article
| Open AccessPeriodic temperature changes drive the proliferation of self-replicating RNAs in vesicle populations
How primordial cells could achieve inheritance of encapsulated components is still an open question. Here, the authors show that ribozymes can assemble in active forms and replicate in populations of membrane vesicles thanks to freeze-thaw cycles.
- Elia Salibi
- , Benedikt Peter
- & Hannes Mutschler
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Article
| Open AccessLigand-specific changes in conformational flexibility mediate long-range allostery in the lac repressor
Using hydrogen-deuterium exchange, the authors propose a model explaining how a classic transcription factor undergoes changes in its conformational ensemble in response to different ligands.
- Anum Glasgow
- , Helen T. Hobbs
- & Tanja Kortemme
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Article
| Open AccessDisease-relevant β2-microglobulin variants share a common amyloid fold
The authors use cryo-EM to determine amyloid fibrils structures of disease relevant variants of β2-microglobulin in vitro. Each variant is polymorphic, but all polymorphs from all samples are built from a a lego-like assembly of common building blocks, suggesting a one amyloid fold’ paradigm.
- Martin Wilkinson
- , Rodrigo U. Gallardo
- & Neil A. Ranson
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Article
| Open AccessPredicting locations of cryptic pockets from single protein structures using the PocketMiner graph neural network
Cryptic pockets enable targeting of proteins currently considered undruggable because they lack pockets in their ground state structures. Here, the authors develop a graph neural network that accurately predicts cryptic pockets in static structures by training using molecular simulation data alone.
- Artur Meller
- , Michael Ward
- & Gregory R. Bowman
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Article
| Open AccessA maximum-entropy model to predict 3D structural ensembles of chromatin from pairwise distances with applications to interphase chromosomes and structural variants
Here the authors develop a computational method based on the maximum entropy principle to construct the structural ensemble of genomes using imaging data. The work reveals three-way contacts between loci and extensive conformational heterogeneity.
- Guang Shi
- & D. Thirumalai
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Article
| Open AccessLinoleic acid improves PIEZO2 dysfunction in a mouse model of Angelman Syndrome
Angelman syndrome (AS) is a neurogenetic disorder. Here, the authors found that PIEZO2 activity is reduced in sensory neurons from a mouse model of AS and used a linoleic acid-enriched diet to enhance PIEZO2 function and ameliorate AS-associated gait deficits.
- Luis O. Romero
- , Rebeca Caires
- & Julio F. Cordero-Morales
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Article
| Open AccessStructural details of a Class B GPCR-arrestin complex revealed by genetically encoded crosslinkers in living cells
The conformation of GPCR-arrestin complexes at the cell membrane, despite available structures, remains uncertain. This work reveals structure and dynamics of the PTH1R-arrestin2 complex, including flexible regions, in live cells.
- Yasmin Aydin
- , Thore Böttke
- & Irene Coin
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Article
| Open AccessDroplet superpropulsion in an energetically constrained insect
Sharpshooters can catapult their droplet excreta with a speed faster than their own movement speed. Challita et al. find that superpropulsion is achieved by the temporal tuning between the droplet and the stylus.
- Elio J. Challita
- , Prateek Sehgal
- & M. Saad Bhamla
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Article
| Open AccessNoncanonical electromechanical coupling paths in cardiac hERG potassium channel
Potassium channels allow vital organ such as brain, heart, and muscles to function. Here, authors reveal the existence of a noncanonical kinematic chain of residues involving the S4/S1 and S1/S5 subunit interfaces that controls the gating of the hERG cardiac channel.
- Carlos A. Z. Bassetto Jr
- , Flavio Costa
- & Alberto Giacomello
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Article
| Open AccessStructure and mechanism of a tripartite ATP-independent periplasmic TRAP transporter
Bacteria and archaea use tripartite ATP-independent periplasmic (TRAP) transporters to import essential nutrients. Davies et al. report a high resolution structure of a TRAP and show that it uses an ‘elevator-with-an operator’ mechanism.
- James S. Davies
- , Michael J. Currie
- & Renwick C. J. Dobson
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Article
| Open AccessSingle-molecular insights into the breakpoint of cellulose nanofibers assembly during saccharification
Lignocellulose recalcitrance hampers its utilization for the production of biofuels and biosourced chemicals. Here, the authors reveal that the amorphous cellulose is the breakpoint of interact microfibrils and propose OsFC16/CESA9 as the engineering target to increase saccharification ability.
- Ran Zhang
- , Zhen Hu
- & Liangcai Peng
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Article
| Open AccessMembrane phospholipids control gating of the mechanosensitive potassium leak channel TREK1
Tandem pore (K2P) potassium channels set the cellular resting membrane potential in tissues throughout the body. Here, authors show how the composition of phospholipid within the bilayer may directly alter gating in this family of ion channels.
- Philipp A. M. Schmidpeter
- , John T. Petroff II
- & Paul M. Riegelhaupt
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Article
| Open AccessThe cofactor-dependent folding mechanism of Drosophila cryptochrome revealed by single-molecule pulling experiments
Characterizing folding pathways of large proteins that bind complex cofactors is challenging. The authors use optical tweezers to study the 542-residue FAD-binding lightsensor protein dCRY, identifying several intermediates and cofactor binding steps, and dissecting the role of FAD moieties in folding.
- Sahar Foroutannejad
- , Lydia L. Good
- & Rodrigo A. Maillard
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Article
| Open AccessA bivalent remipede toxin promotes calcium release via ryanodine receptor activation
Insect toxins with tandem repeats of neurotoxin domains have been found with enhanced receptor avidity. Here, the authors describe a bivalent toxin from remipede venom that targets ryanodine receptors, a rare target for animal venoms.
- Michael J. Maxwell
- , Chris Thekkedam
- & Mehdi Mobli