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| Open AccessA mechanistic reinterpretation of fast inactivation in voltage-gated Na+ channels
Here, authors have identified two pairs of large hydrophobic residues in the channel S6 segments that form the inactivation gate of eukaryotic Na+ channels.
- Yichen Liu
- , Carlos A. Z. Bassetto Jr
- & Francisco Bezanilla
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Article
| Open AccessRedox driven B12-ligand switch drives CarH photoresponse
CarH is a bacterial B12-binding photoreceptor involved in transcriptional regulation. Here, the authors provide insights into B12 dynamics and associated cobalt redox changes following light activation. These demonstrate the CarH response integrates light and oxygen sensing.
- Harshwardhan Poddar
- , Ronald Rios-Santacruz
- & David Leys
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Article
| Open AccessThe net electrostatic potential and hydration of ABCG2 affect substrate transport
ABCG2, an ATP-binding cassette transporter, extrudes hundreds of hydrophilic and hydrophobic compounds from cells, playing roles in xenobiotic clearance or multidrug resistance in cancer. Gose et al provide key insights into ABCG2 substrate selection.
- Tomoka Gose
- , Heather M. Aitken
- & John D. Schuetz
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Article
| Open AccessCrystal structures of MHC class I complexes reveal the elusive intermediate conformations explored during peptide editing
The unusual crystal structures of MHC I-peptide complexes provide a visualization of the remarkable ability of the groove to adapt conformationally to bound peptides, explaining how MHC I molecules edit peptides in antigen presentation.
- Lenong Li
- , Xubiao Peng
- & Marlene Bouvier
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Article
| Open AccessLigand recognition and G protein coupling of the human itch receptor MRGPRX1
MRGPRX1 is a key GPCR expressed in the DRG for itch perception, generating scratch or avoidance behaviors. Here, authors provide structural and pharmacological insights into itch sensation, activation and G-protein signaling downstream of MRGPRX1.
- Lulu Guo
- , Yumu Zhang
- & Jin-Peng Sun
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Article
| Open AccessMulticolor lifetime imaging and its application to HIV-1 uptake
Multicolor imaging employing genetically-encodable fluorescent proteins permits spatiotemporal live cell imaging of multiple cues. Here, authors use multicolor lifetime imaging to visualize quadruple-labelled human immunodeficiency viruses within cellular contexts.
- Tobias Starling
- , Irene Carlon-Andres
- & Sergi Padilla-Parra
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Article
| Open AccessQuantitative real-time in-cell imaging reveals heterogeneous clusters of proteins prior to condensation
The nucleation of biomolecular condensates is seldom quantified in living cells. Here, the authors show how protein clusters form before microscopically visible condensation and find a flat free-energy profile with active blocking of cluster growth.
- Chenyang Lan
- , Juhyeong Kim
- & Thorsten Hugel
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Article
| Open AccessMolecular mechanism underlying regulation of Arabidopsis CLCa transporter by nucleotides and phospholipids
CLC transporters are regulated by nucleotides and phospholipids. Here cryo-EM structure of Arabidopsis CLCa in complex with ATP and PIP2 and electrophysiological analysis suggests the underlying regulatory mechanisms of both nucleotides and phospholipids.
- Zhao Yang
- , Xue Zhang
- & Peng Zhang
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Article
| Open AccessIdentification of a drug binding pocket in TMEM16F calcium-activated ion channel and lipid scramblase
TMEM16F is a Ca2+ activated ion channel and lipid scramblase involved in cell fusion. Here authors determine cryo-EM structures of TMEM16F with or without bound blockers, such as the FDA-approved drug niclosamide.
- Shengjie Feng
- , Cristina Puchades
- & Lily Yeh Jan
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Article
| Open AccessStructural basis of agonist specificity of α1A-adrenergic receptor
α1-adrenergic receptors (α1- AR) play critical roles in the cardiovascular and nervous systems. Here, the authors report molecular insights into the mechanisms underlying the discrimination between α1A-AR and α1B-AR by the agonist A61603.
- Minfei Su
- , Jinan Wang
- & Xin-Yun Huang
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Matters Arising
| Open AccessAntibiotics and hexagonal order in the bacterial outer membrane
- Georgina Benn
- , Thomas J. Silhavy
- & Bart W. Hoogenboom
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Article
| Open AccessCryo-EM structures of human zinc transporter ZnT7 reveal the mechanism of Zn2+ uptake into the Golgi apparatus
ZnT7 is a Golgi-localized Zn2 + /H+ antiporter. Here the authors present the cryo-EM structures of human ZnT7 in Zn2 + -bound and unbound forms, shedding light on its mechanism of Zn2+ transport.
- Han Ba Bui
- , Satoshi Watanabe
- & Kenji Inaba
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Article
| Open AccessMolecular basis of Mg2+ permeation through the human mitochondrial Mrs2 channel
Mrs2 is a mitochondrial Mg2+ channel that is essential for metabolic function. Here, the authors present cryo-EM structures of human Mrs2 revealing symmetrical pentameric assembly and how Mrs2 permeates Mg2+.
- Ming Li
- , Yang Li
- & Yuequan Shen
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Article
| Open AccessControl of motor landing and processivity by the CAP-Gly domain in the KIF13B tail
Intracellular transport of material along microtubules by kinesin motors is critical for cellular homeostasis. Here the authors uncover a unique role for a specialized kinesin tail domain in directing motor transport along specific microtubule tracks.
- Xiangyu Fan
- & Richard J. McKenney
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Article
| Open AccessMembrane mediated mechanical stimuli produces distinct active-like states in the AT1 receptor
The AT1 GPCR plays an essential role in cardiovascular regulation and may be activated by the peptide AngII as well as membrane stretch. Here, Poudel et al. use molecular simulations to show that membrane-mediated activation produces distinct active-like conformations when compared to activation by AngII.
- Bharat Poudel
- , Rajitha Rajeshwar T
- & Juan M. Vanegas
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Article
| Open AccessNetwork-wide thermodynamic constraints shape NAD(P)H cofactor specificity of biochemical reactions
NADH and NADPH are redox cofactors coexisting in all living cells. Here, the authors present a computational study suggesting that evolved NAD(P)H reaction specificities in E. coli are largely shaped by metabolic network structure enabling maximal thermodynamic driving forces close to the theoretical optimum.
- Pavlos Stephanos Bekiaris
- & Steffen Klamt
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Article
| Open AccessMolecular basis of the pleiotropic effects by the antibiotic amikacin on the ribosome
Here the authors use fast kinetics, X-ray crystallography, and cryo-EM to uncover the mechanism of ribosome inhibition by amikacin and kanamycin. They find that amikacin binds near the P-site tRNA, offering new strategies to fight antibiotic resistance.
- Savannah M. Seely
- , Narayan P. Parajuli
- & Matthieu G. Gagnon
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Article
| Open AccessDeterministic early endosomal maturations emerge from a stochastic trigger-and-convert mechanism
Newly formed endosomes mature into early endosomes by shedding one protein and acquiring another. Here, the authors describe a trigger-and-convert mechanism driven by endosomal collisions and fusions that govern timeliness in ensemble maturations.
- Harrison M. York
- , Kunaal Joshi
- & Senthil Arumugam
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Article
| Open AccessEnergetic robustness to large scale structural fluctuations in a photosynthetic supercomplex
Robust photosynthetic light harvesting occurs in large membrane supercomplexes. Here, the authors show that supercomplexes occupy an unexpectedly large range of conformations yet maintain their efficiency due to specific, critical chlorophylls.
- Dvir Harris
- , Hila Toporik
- & Yuval Mazor
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Article
| Open AccessConformational changes in the essential E. coli septal cell wall synthesis complex suggest an activation mechanism
The divisome is a macromolecular machine composed of more than 30 proteins that controls cell wall constriction during bacterial cell division. Here, the authors provide insights into the structure and dynamics of the divisome core complex using a combination of structure prediction, molecular dynamics simulation, single-molecule imaging, and mutagenesis.
- Brooke M. Britton
- , Remy A. Yovanno
- & Zach Hensel
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Article
| Open AccessPartition complex structure can arise from sliding and bridging of ParB dimers
In many bacteria and plasmids, DNA segregation is controlled by the ParABS system, an essential component of which is the formation of a nucleoprotein complex. Here, making use of recent discoveries, the authors develop a sliding and bridging model to predict the fine structure of this complex.
- Lara Connolley
- , Lucas Schnabel
- & Seán M. Murray
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Article
| Open AccessSubunit gating resulting from individual protonation events in Kir2 channels
Here, authors introduced negative charges in the transmembrane helices in Kir2.2 channels generating pH-dependent sub-conductances. Molecular dynamics simulations show how protonation results in step-wise alterations of ion pooling and hence conductance, appearing as gated substates.
- Grigory Maksaev
- , Michael Bründl-Jirout
- & Colin G. Nichols
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Article
| Open AccessIon selectivity and rotor coupling of the Vibrio flagellar sodium-driven stator unit
In this work, the authors provide mechanistic insights for understanding the sodium-dependent, bacterial flagellar stator unit PomAB ion selectivity, directional rotation, and rotor incorporation in Vibrio spp.
- Haidai Hu
- , Philipp F. Popp
- & Nicholas M. I. Taylor
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Article
| Open AccessA small molecule inhibitor of PTP1B and PTPN2 enhances T cell anti-tumor immunity
Here, the authors demonstrate that inhibition of PTP1B and PTPN2 in tumor cells and T-cells with a small molecule inhibitor represses the growth of immunogenic and cold tumors, and enhances response to anti-PD-1 immunotherapy without promoting immune-related toxicities.
- Shuwei Liang
- , Eric Tran
- & Tony Tiganis
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Article
| Open AccessArchitecture and autoinhibitory mechanism of the plasma membrane Na+/H+ antiporter SOS1 in Arabidopsis
SOS1 is a unique electroneutral Na+ /H+ antiporter at the plasma membrane of higher plants and plays a central role in resisting salt stress. Here, the authors report the structures of SOS1 in occluded state, identify the key autoinhibitory elements, and elucidate their molecular mechanism.
- Yuhang Wang
- , Chengcai Pan
- & Yan Zhao
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Article
| Open AccessCysteines 1078 and 2991 cross-linking plays a critical role in redox regulation of cardiac ryanodine receptor (RyR)
Oxidation of ryanodine receptor calcium channels play a critical role in the onset of many cardiac diseases. Here, authors identify specific amino acids that cause ryanodine receptor malfunction during oxidative stress.
- Roman Nikolaienko
- , Elisa Bovo
- & Aleksey V. Zima
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Article
| Open AccessStructural basis for receptor binding and broader interspecies receptor recognition of currently circulating Omicron sub-variants
SARS-CoV-2 Omicron variant evolves into multiple sub-variants. Here, authors evaluate the binding capacity of these sub-variants to human and animal ACE2s and reveal molecular bases for their receptor binding and broader interspecies recognition.
- Zhennan Zhao
- , Yufeng Xie
- & Jianxun Qi
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Article
| Open AccessGPCRome-wide analysis of G-protein-coupling diversity using a computational biology approach
Selective GPCR-G protein complexes formation is critical for signal transduction regulation. Here, the authors use a data-driven approach to show that the structures of experimental and predicted complex interfaces inform, at least partially, on G protein binding preferences.
- Marin Matic
- , Pasquale Miglionico
- & Francesco Raimondi
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Article
| Open AccessDual-color DNA-PAINT single-particle tracking enables extended studies of membrane protein interactions
Single-particle tracking (SPT) has revolutionised studies of protein interactions but is often limited by photobleaching. Here, the authors evolve DNA-PAINT-SPT to enable simultaneous dual-colour detection for the quantification of protein dimerization and live cell membrane protein tracking.
- Christian Niederauer
- , Chikim Nguyen
- & Kristina A. Ganzinger
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Article
| Open AccessAllosteric activation of vinculin by talin
Vinculin binding to talin is a key event in focal adhesion dynamics; yet, how vinculin is activated to recruit actin remains unknown. Here, the authors use a multiscale approach to reveal that talin activates vinculin through an intricate allosteric mechanism tightly regulated by force.
- Florian Franz
- , Rafael Tapia-Rojo
- & Frauke Gräter
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Article
| Open AccessThe structural basis of divalent cation block in a tetrameric prokaryotic sodium channel
Divalent cation block is observed in various tetrameric ion channels. Here, authors use X-ray crystallography, electrophysiology and molecular dynamics simulations to reveal the mechanism of the divalent cation block on a prokaryotic sodium channel.
- Katsumasa Irie
- , Yoshinori Oda
- & Yoshinori Fujiyoshi
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Article
| Open AccessWeak acids produced during anaerobic respiration suppress both photosynthesis and aerobic respiration
The processes of photosynthesis, aerobic and anaerobic respiration (fermentation) power life on Earth. Here, using mainly green alga Chlamydomonas, the authors find that the weak acids produced during fermentation could chemically suppress both photosynthesis and aerobic respiration.
- Xiaojie Pang
- , Wojciech J. Nawrocki
- & Lijin Tian
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Article
| Open AccessBiophysical ordering transitions underlie genome 3D re-organization during cricket spermiogenesis
Orsi et al. identify an elegant solution to DNA packing in cricket sperm nuclei, whereby relatively simple biophysical changes in chromatin properties result in a liquid crystal-like twisted spool organization that favors ultracompaction.
- Guillermo A. Orsi
- , Maxime M. C. Tortora
- & Benjamin Loppin
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Article
| Open AccessDiscovering functionally important sites in proteins
An important step in understanding and using proteins is to identify the residues that are important for function. The authors present a machine-learning based method to predict functional sites that leverages and combines the information available in protein sequences and structures.
- Matteo Cagiada
- , Sandro Bottaro
- & Kresten Lindorff-Larsen
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Article
| Open AccessSpatial and functional arrangement of Ebola virus polymerase inside phase-separated viral factories
Here, the authors characterized the phase separation properties and internal structures of intracellular viral factories induced by Ebola virus and correlated these properties to important steps of viral biogenesis.
- Jingru Fang
- , Guillaume Castillon
- & Erica Ollmann Saphire
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Article
| Open AccessCrosstalk between regulatory elements in disordered TRPV4 N-terminus modulates lipid-dependent channel activity
An integrated structural biology approach uncovers the structural complexity of the intrinsically disordered region (IDR) within the TRPV4 ion channel. Multiple stimulatory and inhibitory elements were identified within the IDR that modulate channel activity in a lipid-dependent manner.
- Benedikt Goretzki
- , Christoph Wiedemann
- & Ute A. Hellmich
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Article
| Open AccessStructural and photophysical characterization of the small ultra-red fluorescent protein
Researchers determined the three-dimensional structure of the small Ultra-Red Fluorescent Protein (smURFP) to understand its properties and the previous directed evolution process. In addition, they show smURFP fluoresces longer than small molecules.
- Atanu Maiti
- , Cosmo Z. Buffalo
- & Erik A. Rodriguez
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Article
| Open AccessA model for organization and regulation of nuclear condensates by gene activity
Through a physics-based model framework, the authors propose a central role for the nonequilibrium processes underling gene activity in shaping morphology, dynamics, and regulation of diverse nuclear condensates.
- Halima H. Schede
- , Pradeep Natarajan
- & Krishna Shrinivas
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Article
| Open AccessStructural basis of CXC chemokine receptor 1 ligand binding and activation
Chemokines are small proteins secreted at sites of injury. Here, the authors describe the structure of the chemokine receptor CXCR1 bound to chemokine CXCL8, solved by cryo-EM. The model helps explain the ligand preferences of this receptor.
- Naito Ishimoto
- , Jae-Hyun Park
- & Sam-Yong Park
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Article
| Open AccessPredicting scale-dependent chromatin polymer properties from systematic coarse-graining
Here the authors provide a quantitative description of chromatin as bead-spring polymers. The study predicts the 3D size of chromatin beads given the genomic length and computes how stretchable and bendable chromatin is and how soft chromatin beads are.
- Sangram Kadam
- , Kiran Kumari
- & Ranjith Padinhateeri
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Article
| Open AccessMechanism of ATP hydrolysis dependent rotation of bacterial ATP synthase
The ATP synthase FoF1 undergoes rotation in discrete 120° steps. Using cryo-EM analysis, the authors characterise intermediate structures within these 120° steps at 81°, 83°, 91°, and 101°. This shows that FoF1 undergoes a total of 15 steps in a 360° rotation, exhibiting multiple discreet movements per full rotation as opposed to one fluid motion.
- Atsuki Nakano
- , Jun-ichi Kishikawa
- & Ken Yokoyama
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Article
| Open AccessEstablishing mammalian GLUT kinetics and lipid composition influences in a reconstituted-liposome system
Transport assays using purified glucose transporters (GLUTs) have proven to be difficult to implement, hampering deeper mechanistic insights. Here the authors have optimized a transport assay in liposomes that will provide insight to study other membrane transport proteins.
- Albert Suades
- , Aziz Qureshi
- & David Drew
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Article
| Open AccessLateral membrane organization as target of an antimicrobial peptidomimetic compound
The mechanism of action of the antibacterial tripeptide AMC-109 is unclear. Here, Melcrová et al. show that AMC-109 self-assembles into stable aggregates with a cationic surface, and then individual peptides insert into the bacterial membrane and disrupt membrane nanodomains, thus affecting membrane function without forming pores.
- Adéla Melcrová
- , Sourav Maity
- & Wouter H. Roos
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Article
| Open AccessMulticomponent regulation of actin barbed end assembly by twinfilin, formin and capping protein
Actin networks in eukaryotic cells mediate essential processes such as cell migration, endocytosis, and morphogenesis. Here, using microfluidics assisted TIRF microscopy, the authors investigate how actin barbed-end polymerases, cappers, and depolymerases cooperate to regulate assembly of these networks.
- Heidi Ulrichs
- , Ignas Gaska
- & Shashank Shekhar
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Article
| Open AccessProfiling of basal and ligand-dependent GPCR activities by means of a polyvalent cell-based high-throughput platform
Interrogating the dynamic and functionally diverse signaling of GPCRs requires comprehensive cellular tools. Here Zeghal et al. develop Tango-Trio, a screening platform capable of profiling basal and drug-activated activities at hundreds of GPCRs.
- Manel Zeghal
- , Geneviève Laroche
- & Patrick M. Giguère
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Article
| Open AccessCryo-EM and femtosecond spectroscopic studies provide mechanistic insight into the energy transfer in CpcL-phycobilisomes
CpcL-phycobilisome (PBS) is a type of small PBS that transfers energy directly to photosystem I (PSI) without a core structure. Here the authors combine cryo-electron microscopy and ultrafast spectroscopy to explore energy transfer pathway in CpcL-PBS.
- Lvqin Zheng
- , Zhengdong Zhang
- & Jindong Zhao
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Article
| Open AccessA mechanical-coupling mechanism in OSCA/TMEM63 channel mechanosensitivity
Mechanosensitive channels exhibit large structural variations. Here, the authors reveal that OSCA channels exhibit different oligomeric states and are gated/regulated by lipids at different locations in response to physical forces.
- Mingfeng Zhang
- , Yuanyue Shan
- & Duanqing Pei
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Article
| Open AccessNuclear lamina strain states revealed by intermolecular force biosensor
In this work, a nanobody based intermolecular strain sensor was used to follow the mechanical strain in the nuclear lamina. The results indicate that mechanical state of the nuclear lamina is not only affected by the cell contractility, but also chromatin packing.
- Brooke E. Danielsson
- , Bobin George Abraham
- & Teemu O. Ihalainen
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Article
| Open AccessFast-exchanging spirocyclic rhodamine probes for aptamer-based super-resolution RNA imaging
Live-cell RNA imaging with high spatial and temporal resolution remains a major challenge. Here the authors design spirocyclic rhodamine probes that enable a fluorescent light-up aptamer system suitable for visualizing RNAs in live or fixed cells with two different super-resolution microscopy modalities SMLM and STED.
- Daniel Englert
- , Eva-Maria Burger
- & Murat Sunbul