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| Open AccessStructure of human CALHM1 reveals key locations for channel regulation and blockade by ruthenium red
The voltage-dependent CALHM1 channel is critical in neuromodulation and gustatory signaling. The authors present cryo-EM structures of human CALHM1 in apo- and blocked-states. They explore effects of lipid binding on channel structure and activity.
- Johanna L. Syrjänen
- , Max Epstein
- & Hiro Furukawa
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Article
| Open AccessTRPV4-Rho GTPase complex structures reveal mechanisms of gating and disease
Despite TRPV4’s medical importance, the mechanisms of ligand-mediated channel gating and its regulation by Rho GTPase are unclear. Here, the authors report the structures of TRPV4 in complex with RhoA and ligands, offering atomic-level insights into their functions.
- Do Hoon Kwon
- , Feng Zhang
- & Seok-Yong Lee
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Article
| Open AccessRapid and reversible optical switching of cell membrane area by an amphiphilic azobenzene
The surface area of living cells is tightly regulated. Here, authors show that the surface area and shape of cells can be reversibly manipulated with light using amphiphilic molecular photoswitches that enter and leave the membrane.
- Fabian Höglsperger
- , Bart E. Vos
- & Bart Jan Ravoo
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Article
| Open AccessMechanistic insights into the aggregation pathway of the patient-derived immunoglobulin light chain variable domain protein FOR005
Using solution-state NMR spectroscopy, the authors followed the individual steps involved in protein misfolding from the native to the amyloid fibril state for the antibody light chain (AL) amyloidosis related protein FOR005.
- Tejaswini Pradhan
- , Riddhiman Sarkar
- & Bernd Reif
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Article
| Open AccessMutagenesis and structural studies reveal the basis for the specific binding of SARS-CoV-2 SL3 RNA element with human TIA1 protein
Here the authors reveal the binding interface for the SARS-CoV-2 SL3 RNA element to human TIA1 protein and find that disruptions of the identified viral RNA-host protein interactions with designed ASOs reduce SARS-CoV-2 infection in cells.
- Dong Zhang
- , Lulu Qiao
- & Ruhong Zhou
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Article
| Open AccessHow soluble misfolded proteins bypass chaperones at the molecular level
How soluble misfolded proteins can bypass chaperones is unknown. Utilizing a meta-analysis, multi-scale modelling, and new experimental data it is found that this phenomena is common and arises from misfolded states that are native-like and long-lived due to protein self-entanglements.
- Ritaban Halder
- , Daniel A. Nissley
- & Edward P. O’Brien
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Article
| Open AccessCyclic di-AMP traps proton-coupled K+ transporters of the KUP family in an inward-occluded conformation
Second messengers regulate a broad spectrum of processes in bacteria. Here, authors characterize how the second messenger cyclic di-AMP inhibits the potassium transporter KimA using cryo-EM, molecular dynamics simulations and functional assays.
- Michael F. Fuss
- , Jan-Philip Wieferig
- & Inga Hänelt
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Article
| Open AccessDynamic interplay between target search and recognition for a Type I CRISPR-Cas system
The details of CRISPR-Cas target search are unresolved. Here the authors analyse the target search process of the Type I CRISPR-Cas complex Cascade: they show that target search and target recognition are tightly linked, and DNA supercoiling and limited 1D diffusion play a role.
- Pierre Aldag
- , Marius Rutkauskas
- & Ralf Seidel
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Article
| Open AccessStructure and dynamics of an archetypal DNA nanoarchitecture revealed via cryo-EM and molecular dynamics simulations
DNA can be folded into rationally designed, unique, and functional materials. Here the authors analyse an archetypal DNA nanoarchitecture with single particle cryo-electron microscopy and molecular dynamics simulations.
- Katya Ahmad
- , Abid Javed
- & Stefan Howorka
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Article
| Open AccessCannabidiol inhibits Nav channels through two distinct binding sites
Cannabidiol (CBD), the nonpsychoactive component in cannabis, is an effective treatment for epilepsy and pain. Here, authors explored the mode of action of CBD on hNav1.7 channels through two distinct binding sites, suggesting a direct stabilization of the inactivated state of channels.
- Jian Huang
- , Xiao Fan
- & Nieng Yan
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Article
| Open AccessStructure and proposed DNA delivery mechanism of a marine roseophage
Tailed bacteriophages account for the majority of all phages. Here, the authors employ cryo-EM and structure prediction techniques to investigate the atomic structure of the R4C phage capsid and the in- situ structure of its unique long rigid tail.
- Yang Huang
- , Hui Sun
- & Ningshao Xia
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Article
| Open AccessThe inhibition mechanism of the SUR2A-containing KATP channel by a regulatory helix
Cardiac KATP channels consisting of SUR2A are poorly activated by Mg-ADP compared to other subtypes. Here, the authors present structures of SUR2A and SUR2B, uncovering a regulatory helix that inhibits SUR2A activation.
- Dian Ding
- , Tianyi Hou
- & Lei Chen
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Article
| Open AccessAtomic model for core modifying region of human fatty acid synthase in complex with Denifanstat
Here, the authors develop a protein engineering method that enables high-resolution structural biology study of human fatty acid synthase. Using this technique, they uncover unique structural features of the enzyme and the mechanism of its inhibition by an anticancer drug Denifanstat.
- S. M. Naimul Hasan
- , Jennifer W. Lou
- & Mohammad T. Mazhab-Jafari
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Article
| Open AccessAllosteric activation of cell wall synthesis during bacterial growth
Coordination of cell wall assembly is critical for bacterial morphology and survival. Here, the authors show that activation of cell wall synthesis by the Rod complex is regulated by the structural dynamics of RodA-PBP2.
- Irina Shlosman
- , Elayne M. Fivenson
- & Joseph J. Loparo
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Article
| Open AccessSubstrate binding-induced conformational transitions in the omega-3 fatty acid transporter MFSD2A
Molecular mechanisms of MFSD2A-mediated lysolipid transport into the brain has been elusive. Here, using molecular dynamics, the authors uncover how initial stages of transport cycle are enabled by substrate-induced conformational changes in MFSD2A.
- Shana Bergman
- , Rosemary J. Cater
- & George Khelashvili
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Article
| Open AccessStructural mechanism of intracellular autoregulation of zinc uptake in ZIP transporters
Zinc uptake and regulation are vital in all life forms. Here, authors describe a dimer of a ZIP-family zinc transporter in an inward-facing, inhibited conformation. A built-in zinc sensor is proposed to sense the intracellular zinc content to autoregulate zinc uptake across membranes.
- Changxu Pang
- , Jin Chai
- & Qun Liu
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Article
| Open AccessCryo-EM structures of ClC-2 chloride channel reveal the blocking mechanism of its specific inhibitor AK-42
AK-42 was reported as a specific inhibitor of ClC-2 but its working mechanism is not clear. Here authors report cryo-EM structures of apo ClC-2 and in complex with AK-42, revealing how it inhibits ClC-2 specifically.
- Tao Ma
- , Lei Wang
- & Huawei Zhang
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Article
| Open AccessInflationary theory of branching morphogenesis in the mouse salivary gland
The authors show that the ramified ductal network of the mouse salivary gland develops from a set of simple probabilistic rules, where ductal elongation and branching are driven by the persistent expansion of the surrounding tissue.
- Ignacio Bordeu
- , Lemonia Chatzeli
- & Benjamin D. Simons
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Article
| Open AccessStabilization of pre-existing neurotensin receptor conformational states by β-arrestin-1 and the biased allosteric modulator ML314
The authors highlight the importance of kinetics in GPCR activation. Using solution NMR, they show that the transducer βarrestin1 and the β-arrestin1biased ligand ML314 kinetically tune the conformational ensemble of the neurotensin receptor 1.
- Fabian Bumbak
- , James B. Bower
- & Joshua J. Ziarek
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Article
| Open AccessNative American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain
Drugs that rescue function of episodic ataxia 1 (EA1) mutant potassium channels are lacking. Here, Manville et al identify and describe the molecular basis for Native American botanical ataxia remedies that directly rescue EA1 mutant channels.
- Rían W. Manville
- , J. Alfredo Freites
- & Geoffrey W. Abbott
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Article
| Open AccessDownregulation of extraembryonic tension controls body axis formation in avian embryos
Extraembryonic tissues provide structural support in addition to signaling inputs. Here they show that extraembryonic structures regulate the mechanical environment of the developing chicken embryo, wherein weakening of the vitelline membrane permits tissue movements that form the body axis.
- Daniele Kunz
- , Anfu Wang
- & Fengzhu Xiong
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Article
| Open AccessStructural mapping of Nav1.7 antagonists
Voltage-gated sodium (Nav) channels are targeted by various clinically applied and investigational drugs. Here cryo-EM structures of Nav1.7 bound to 7 compounds with diverse chemical skeletons reveal the structural basis of action of these drugs and provide a 3D structural map for drug binding sites on Nav channels.
- Qiurong Wu
- , Jian Huang
- & Nieng Yan
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Article
| Open AccessStructural insights into perilipin 3 membrane association in response to diacylglycerol accumulation
Perilipin 3 binds to emerging lipid droplets from the endoplasmic reticulum. Choi and Ajjaji et al characterize the molecular mechanisms of Perilipin 3 recruitment to membranes and uncover a function for the PAT domain in diacylglycerol sensing.
- Yong Mi Choi
- , Dalila Ajjaji
- & Michael V. Airola
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Article
| Open AccessStructural interplay of anesthetics and paralytics on muscle nicotinic receptors
Here the authors use a structural approach to reveal how neuromuscular blockers and a general anesthetic antagonize the muscle-type nicotinic receptor through competitive and allosteric mechanisms.
- Umang Goswami
- , Md Mahfuzur Rahman
- & Ryan E. Hibbs
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Article
| Open AccessCryo-EM structure of the folded-back state of human β-cardiac myosin
The authors report the high-resolution structure of human β-cardiac myosin in its sequestered state. The results provide insights into the cardiac regulation and represent a tool to investigate the development of inherited cardiomyopathies.
- Alessandro Grinzato
- , Daniel Auguin
- & Julien Robert-Paganin
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Article
| Open AccessA mutation in switch I alters the load-dependent kinetics of myosin Va
Myosin transduces chemical energy into mechanical work, but the mechanism remains unclear. In this work, the authors show that force-generation precedes product release and that a mutation in the active site alters the load dependence of product release.
- Christopher Marang
- , Brent Scott
- & Edward P. Debold
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Article
| Open AccessStructures of Tetrahymena thermophila respiratory megacomplexes on the tubular mitochondrial cristae
Tetrahymena thermophila possesses tubular mitochondrial cristae and a highly divergent electron transport chain. Here the authors report cryo-EM structures of its half ring-shaped ~8 MDa megacomplex IV2 + (I + III2 + II)2 and ~10.6 MDa megacomplex (IV2 + I + III2 + II)2 adapted to the cristae membrane curvature.
- Fangzhu Han
- , Yiqi Hu
- & Long Zhou
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Article
| Open AccessThe AE4 transporter mediates kidney acid-base sensing
Maintaining systemic acid-base balance is a central task of the kidneys, but it is still undetermined how acid-base alterations are perceived by the kidney. Here, the authors show that the solute transporter AE4 in β-intercalated cells is an essential part of the renal acid-base sensing mechanism
- H. Vitzthum
- , M. Koch
- & H. Ehmke
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Article
| Open AccessAsymmetric pendrin homodimer reveals its molecular mechanism as anion exchanger
Pendrin SLC26A4 plays an important role for anion balance. Here, authors resolve cryo-EM structures of pendrin performing co-incident uptake and secretion of anions, providing a structural basis of this anion exchange mechanism.
- Qianying Liu
- , Xiang Zhang
- & Zhenguo Chen
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Article
| Open AccessEarly events in amyloid-β self-assembly probed by time-resolved solid state NMR and light scattering
Here the authors report time-resolved experiments showing that amyloid-β peptide molecules become partially structured even before they adhere to one another, within one millisecond. Peptide conformations change only slightly as assemblies grow in size for many minutes.
- Jaekyun Jeon
- , Wai-Ming Yau
- & Robert Tycko
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Article
| Open AccessCo-crystal structures of the fluorogenic aptamer Beetroot show that close homology may not predict similar RNA architecture
The recently discovered aptamer Beetroot is a homodimeric RNA that binds and activates DFAME, a conditional, red-shifted fluorophore derived from GFP. Here the authors determine the Beetroot-DFAME co-crystal structure, which is distinctively different from that of similar RNA aptamer Corn.
- Luiz F. M. Passalacqua
- , Mary R. Starich
- & Adrian R. Ferré-D’Amaré
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Article
| Open AccessAnt venoms contain vertebrate-selective pain-causing sodium channel toxins
Stings of certain ant species can cause intense, long-lasting nociception. Here, authors show that the major contributors of these symptoms are vertebrate-selective defensive venom peptides which modulate the activity of voltage-gated sodium channels.
- Samuel D. Robinson
- , Jennifer R. Deuis
- & Irina Vetter
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Article
| Open AccessWetting and complex remodeling of membranes by biomolecular condensates
In this work, the authors investigated on the interaction of biomolecular condensates with membranes and report that they can exhibit two wetting transitions modulated by membrane or milieu composition. Condensate adhesion can trigger intriguing ruffling of the membrane interface into complex finger-like structures.
- Agustín Mangiarotti
- , Nannan Chen
- & Rumiana Dimova
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Article
| Open AccessChemo-mechanical diffusion waves explain collective dynamics of immune cell podosomes
Dendritic cells can utilize the dynamics of podosomes to probe their microenvironment. Here, the authors propose a chemo-mechanical model for the height oscillations of individual podosomes and the collective wave dynamics in a podosome cluster.
- Ze Gong
- , Koen van den Dries
- & Vivek B. Shenoy
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Article
| Open AccessMembrane compression by synaptic vesicle exocytosis triggers ultrafast endocytosis
The authors describe the mechanism of exo-endocytosis coupling at synapses. They find that actin forms a ring around the region of exocytosis. This ring conserves membrane area, allowing induction of inward membrane buckling following exocytosis.
- Tyler H. Ogunmowo
- , Haoyuan Jing
- & Jian Liu
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Article
| Open AccessAntibody binding reports spatial heterogeneities in cell membrane organization
The organization of proteins and sugars on the cell membrane is crucial for cell signaling and function. Here, authors develop molecular probes and simulations to characterize the spatial organization of macromoleucles on live cell membranes.
- Daniel P. Arnold
- , Yaxin Xu
- & Sho C. Takatori
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Article
| Open AccessMolecular mechanism of hyperactivation conferred by a truncation of TRPA1
A drastic TRPA1 mutant was identified in patients with CRAMPT syndrome, but it has not been functionally characterized. Here, the authors find this mutant confers gain-of-function by co-assembling with wild type protein to form hyperactive channels.
- Avnika Bali
- , Samantha P. Schaefer
- & Candice E. Paulsen
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Article
| Open AccessCharacterisation of IL-23 receptor antagonists and disease relevant mutants using fluorescent probes
The single nucleotide polymorphism C115Y in the IL-23 receptor is associated with autoinflammatory diseases. Here the authors demonstrate that this mutation prevents the binding of a fluorescent cyclic peptide and IL-23 to the IL-23 receptor.
- Charles S. Lay
- , Albert Isidro-Llobet
- & Stephen J. Hill
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Article
| Open AccessAutophagy receptor NDP52 alters DNA conformation to modulate RNA polymerase II transcription
An autophagy receptor, NDP52, is recruited to the nucleus where it can bind DNA. The authors show this promotes changes in chromatin accessibility which supports transcription initiation, providing a direct link between autophagy and transcription regulation.
- Ália dos Santos
- , Daniel E. Rollins
- & Christopher P. Toseland
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Article
| Open AccessStructural basis of epitope selectivity and potent protection from malaria by PfCSP antibody L9
The cryo-EM structure of the highly potent malaria antibody L9 reveals a key role of light-chain derived homotypic interactions in antigen binding and parasite inhibition, enabling antibody engineering and next-generation malaria vaccine design.
- Gregory M. Martin
- , Monica L. Fernández-Quintero
- & Andrew B. Ward
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Article
| Open AccessStructural insights into cardiolipin replacement by phosphatidylglycerol in a cardiolipin-lacking yeast respiratory supercomplex
Whether anionic phospholipids required for respiratory supercomplex (SC) formation is unclear. Here authors resolve SCs from a wild type and cardiolipin-deficient yeast strain at 3.2- 3.3 Å resolution to show that cardiolipin can be replaced by phosphatidylglycerol.
- Corey F. Hryc
- , Venkata K. P. S. Mallampalli
- & William Dowhan
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Article
| Open AccessDynamic conformational switching underlies TFIIH function in transcription and DNA repair and impacts genetic diseases
The study unveils the structure, dynamics and regulatory mechanisms of the TFIIH protein assembly underpinning its divergent functions in gene expression and genome maintenance. Models link positions of TFIIH mutations to genetic disease phenotypes.
- Jina Yu
- , Chunli Yan
- & Ivaylo Ivanov
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Article
| Open AccessVesicular glutamate transporters are H+-anion exchangers that operate at variable stoichiometry
In glutamatergic neurons, synaptic vesicles contain glutamate, but not aspartate. Here, the authors show that vesicular glutamate transporters are H+/anion exchangers that attain high selectivity for glutamate via variable transport coupling.
- Bettina Kolen
- , Bart Borghans
- & Christoph Fahlke
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Article
| Open AccessTwo single-point mutations in Ankyrin Repeat one drastically change the threshold temperature of TRPV1
TRPV1 is a noxious heat sensor. Here, authors showed that tailed amphibians express TRPV1 with a reduced heat-activation threshold by substitution of two amino acids in the N-terminal region to contribute to cool-habitat selection.
- Shogo Hori
- , Michihiro Tateyama
- & Osamu Saitoh
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Article
| Open AccessStructural mechanism of human oncochannel TRPV6 inhibition by the natural phytoestrogen genistein
The authors report the structure of human oncochannel TRPV6 in complex with the plant derived phytoestrogen genistein. The structure provides insights into genistein binding in the channel pore, and how it acts as blocker and gating modifier, suggesting a mechanism of inhibition that can be explored for the structure-based drug design.
- Arthur Neuberger
- , Yury A. Trofimov
- & Alexander I. Sobolevsky
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Article
| Open AccessLipid flipping in the omega-3 fatty-acid transporter
Lipid flipping across membrane leaflets are vital yet enigmatic biological processes. Here, five cryo-EM structures provide snapshots to delineate a mechanism of omega-3 fatty acid flipping across the blood brain barrier.
- Chi Nguyen
- , Hsiang-Ting Lei
- & Tamir Gonen
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Article
| Open AccessStructural mechanisms of TRPM7 activation and inhibition
Authors present the structural mechanisms of TRPM7 spontaneous and agonist-induced opening and inhibition by potent and selective antagonists.
- Kirill D. Nadezhdin
- , Leonor Correia
- & Alexander I. Sobolevsky
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Article
| Open AccessMolecular determinants of inhibition of UCP1-mediated respiratory uncoupling
Combining molecular dynamic simulations with in vivo functional assays, Gagelin et al. identified unique molecular features of the mitochondrial carrier uncoupling protein 1 that are crucial to its inhibition by nucleotides
- Antoine Gagelin
- , Corentin Largeau
- & Bruno Miroux
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Article
| Open AccessCatch bond models may explain how force amplifies TCR signaling and antigen discrimination
Catch bonds where lifetime increases with force applied can form when T cell receptors (TCR) interact with agonist peptide-MHC (pMHC) complexes. Here the authors use a modelling and experimental approach to analyse 55 TCR–pMHC bond lifetime curves measured under force to further characterise the structural bases and functional relevance of catch bonds.
- Hyun-Kyu Choi
- , Peiwen Cong
- & Cheng Zhu