Featured
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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 AccessStructural insights into ligand recognition and activation of the medium-chain fatty acid-sensing receptor GPR84
The orphan GPR84 plays important roles in inflammation, fibrosis, and metabolism. Here, authors report cryo-EM structures of the receptor bound to two ligands, with insights into ligand binding and entry from the extracellular milieu.
- Heng Liu
- , Qing Zhang
- & Wanchao Yin
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Article
| Open AccessPIE-seq: identifying RNA-binding protein targets by dual RNA-deaminase editing and sequencing
Tracking protein-RNA interaction across cell types is challenging. Here, Ruan et al develop a dual-deaminase method called PIE-Seq, where protein targets are marked by both C-to-U and A-to-I RNA base editors, and apply it to 25 human RNA-binding proteins.
- Xiangbin Ruan
- , Kaining Hu
- & Xiaochang Zhang
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Matters Arising
| Open AccessThe G protein preference of orexin receptors is currently an unresolved issue
- Jyrki P. Kukkonen
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Matters Arising
| Open AccessReply to: The G protein preference of orexin receptors is currently an unresolved issue
- Jie Yin
- , Yanyong Kang
- & Daniel M. Rosenbaum
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Article
| Open AccessIncreased renal elimination of endogenous and synthetic pyrimidine nucleosides in concentrative nucleoside transporter 1 deficient mice
Concentrative nucleoside transporters (CNTs) are cellular nucleoside influx systems, but their in vivo roles are poorly defined. By generating CNT1 knockout (KO) mice, here the authors show a role of CNT1 in the renal reabsorption of endogenous and synthetic nucleosides.
- Avinash K. Persaud
- , Matthew C. Bernier
- & Rajgopal Govindarajan
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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 AccessStructures of active Hantaan virus polymerase uncover the mechanisms of Hantaviridae genome replication
Hantaan virus is a lifethreatening Bunyavirus. Here the authors determine the cryoelectron microscopy structure of its polymerase, a central enzyme involved in viral genome replication. Structures combined with in vitro activity decipher at high resolution the molecular mechanisms of the replication cycle.
- Quentin Durieux Trouilleton
- , Sergio Barata-García
- & Hélène Malet
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Article
| Open AccessStructures of human SGLT in the occluded state reveal conformational changes during sugar transport
SGLT plays key roles in sugar uptake and reabsorption. Here the authors provided the cryo-EM structures of human SGLT1 and SGLT2 in the substrate-bound occluded state, uncovering the conformational changes of SGLT during sugar transport.
- Wenhao Cui
- , Yange Niu
- & Lei Chen
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Article
| Open AccessDesigned active-site library reveals thousands of functional GFP variants
Mutations in a protein active site can alter function in useful ways, but the active site is sensitive to changes. Here the authors present a general strategy to design combinatorial mutation libraries. Applied to GFP, the authors isolate thousands of fluorescent designs that exhibit large and useful changes in spectral properties.
- Jonathan Yaacov Weinstein
- , Carlos Martí-Gómez
- & Sarel J. Fleishman
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Article
| Open AccessComputational design of dynamic receptor—peptide signaling complexes applied to chemotaxis
Engineering protein biosensors that respond to biomolecules by triggering cellular responses has largely relied on binding rigid molecules. Here, the authors develop a computational strategy for designing signaling complexes between conformationally dynamic proteins and peptides.
- Robert E. Jefferson
- , Aurélien Oggier
- & Patrick Barth
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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 AccessLigand dependent interaction between PC-TP and PPARδ mitigates diet-induced hepatic steatosis in male mice
Deletion of PC-TP has many beneficial effects, mostly ascribed to its role in regulating THEM2. Here, the authors show a novel interaction between PC-TP and PPARδ that explains aspects of the beneficial metabolic phenotype associated with PC-TP deletion.
- Samuel A. Druzak
- , Matteo Tardelli
- & Eric A. Ortlund
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Article
| Open AccessMolecular basis for recognition and deubiquitination of 40S ribosomes by Otu2
Otu2-driven deubiquitylation of ribosomal protein eS7 impacts translational efficiency. Here, the authors provide the molecular basis for recognition of monoubiquitinated eS7 on 40S and give mechanistic insights into Otu2’s role in translation reset.
- Ken Ikeuchi
- , Nives Ivic
- & Roland Beckmann
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Article
| Open AccessA first-in-class inhibitor of Hsp110 molecular chaperones of pathogenic fungi
Hsp110 chaperones play important roles in protein homeostasis in eukaryotes. Here, the authors identify a small compound that inhibits fungal Hsp110s as well as the growth and viability of the pathogenic fungus Candida albicans, supporting Hsp110s as targets for development of new antifungal drugs.
- Liqing Hu
- , Cancan Sun
- & Qinglian Liu
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Article
| Open AccessReplication fork binding triggers structural changes in the PriA helicase that govern DNA replication restart in E. coli
The mechanism of replication restart initiation by the bacterial DNA replication restart proteins PriA and PriB is resolved, revealing a switch-like restructuring of PriA triggered by replication fork binding that mediates PriA/PriB complex assembly.
- Alexander T. Duckworth
- , Peter L. Ducos
- & James L. Keck
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Article
| Open AccessMetal3D: a general deep learning framework for accurate metal ion location prediction in proteins
Zinc is an essential metal for many proteins. Here, the authors propose a model based on 3D convolutional networks to predict the location of zinc in experimental and computationally predicted structures within a framework readily extensible to other metals.
- Simon L. Dürr
- , Andrea Levy
- & Ursula Rothlisberger
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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 AccessStructural basis for activation of CB1 by an endocannabinoid analog
This manuscript describes the structure of an endocannabinoid analog-bound CB1 complex and reveals the structural determinants of ligand efficacy. The activation mechanism, unique to CB1, that is exploited by allosteric modulators is also outlined.
- Kaavya Krishna Kumar
- , Michael J. Robertson
- & Brian Kobilka
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Article
| Open AccessLigand-induced activation and G protein coupling of prostaglandin F2α receptor
Prostaglandin F2α receptor (FP) is the primary therapeutic target for glaucoma and several other diseases. Here, the authors reveal structural mechanisms of ligand recognition, receptor activation, and G protein coupling by FP.
- Canrong Wu
- , Youwei Xu
- & H. Eric Xu
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Article
| Open AccessConfinement of unliganded EGFR by tetraspanin nanodomains gates EGFR ligand binding and signaling
EGFR is a receptor that is upregulated in many cancers, but the mechanisms that control EGFR function are incompletely understood. Here the authors used single particle tracking to identify a role for tetraspanin CD81 in EGFR ligand binding, mobility, and signaling.
- Michael G. Sugiyama
- , Aidan I. Brown
- & Costin N. Antonescu
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Article
| Open AccessInositol pyrophosphates activate the vacuolar transport chaperone complex in yeast by disrupting a homotypic SPX domain interaction
Pipercevic et al resolve how inositol molecules activate the VTC protein complex. The VTC complex stores phosphate in yeast and is controlled by SPX domains. The inositol molecules break an interaction between SPX domains to activate the complex.
- Joka Pipercevic
- , Bastian Kohl
- & Sebastian Hiller
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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 AccessImproving de novo protein binder design with deep learning
Recently, a pipeline for the design of protein-binding proteins using only the structure of the target protein was reported. Here, the authors report that the incorporation of deep learning methods into the original pipeline increases experimental success rate by ten-fold.
- Nathaniel R. Bennett
- , Brian Coventry
- & David Baker
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Article
| Open AccessSymport and antiport mechanisms of human glutamate transporters
Ion gradients power the neurotransmitter transport by brain glutamate transporters. Here, the authors report cryo-EM structures of the EAAT3 transporter isoform with and without the ions and the neurotransmitter, revealing the coupling mechanisms.
- Biao Qiu
- & Olga Boudker
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Article
| Open AccessNucleotide exchange is sufficient for Hsp90 functions in vivo
A complete understanding of the role of ATP hydrolysis in Hsp90 function is elusive. Here, the authors show that ATP hydrolysis, but not binding, is dispensable for essential or specialized Hsp90 functions in vivo, shedding new light on this mystery.
- Michael Reidy
- , Kevin Garzillo
- & Daniel C. Masison
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Article
| Open AccessA visual opsin from jellyfish enables precise temporal control of G protein signalling
Jellyfish see light in a similar way that vertebrates smell odours. Here, Michiel van Wyk and Sonja Kleinlogel show how jellyfish has adapted this slow signal detection pathway to support sophisticated vision, and use a similar method to restore vision in blind mice.
- Michiel van Wyk
- & Sonja Kleinlogel
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Article
| Open AccessPain-causing stinging nettle toxins target TMEM233 to modulate NaV1.7 function
Voltage-gated sodium channels function as multiprotein signaling complexes. Here, authors show that the dispanin TMEM233 is essential for activity of stinging nettle toxins and that co-expression of TMEM233 modulates the gating properties of NaV1.7.
- Sina Jami
- , Jennifer R. Deuis
- & Irina Vetter
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Article
| Open AccessThe AAV capsid can influence the epigenetic marking of rAAV delivered episomal genomes in a species dependent manner
rAAV vectors vary in their effectiveness between species, making it difficult to predict clinical outcomes. Here authors show that AAV capsid proteins influence the vector epigenomic state in cells, and that a single amino acid change in the vector can alter the vector epigenome and hence transgene expression levels between species.
- Adriana Gonzalez-Sandoval
- , Katja Pekrun
- & Mark A. Kay
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Review Article
| Open AccessEngineering protein-based therapeutics through structural and chemical design
Ebrahimi and Samanta review the key advances in the chemical and structural modification of proteins that have enabled their rise as indispensable tools in medicine and outline emerging protein engineering strategies that can potentially unlock structures with improved therapeutic properties.
- Sasha B. Ebrahimi
- & Devleena Samanta
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Article
| Open AccessSequence-structure-function relationships in the microbial protein universe
Advances in protein structure prediction have led to a significant influx of protein structure data. Here the authors exploit this data to offer an unbiased overview of complex sequence-structure-function relationships in the protein universe. This work opens up new uses for 3D structure data repositories in meta-omics and other fields of biology.
- Julia Koehler Leman
- , Pawel Szczerbiak
- & Tomasz Kosciolek
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Article
| Open AccessLarge-scale phage-based screening reveals extensive pan-viral mimicry of host short linear motifs
Protein-protein interactions underlie all aspects of a viral infection. Here the authors employ a pan-viral approach for systematic identification of motif-mediated interactions between viral and human proteins and show that the information can be used to find targets for antiviral drug development.
- Filip Mihalič
- , Leandro Simonetti
- & Ylva Ivarsson
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Article
| Open AccessDesigned Rubredoxin miniature in a fully artificial electron chain triggered by visible light
Living organisms regulate their energy demand by managing electron trafficking in complex transport chains. Here, the authors pioneer a fully artificial electron chain triggered by visible light using designed proteins, unlocking possibilities in bioengineering.
- Marco Chino
- , Luigi Franklin Di Costanzo
- & Vincenzo Pavone
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Article
| Open AccessLow complexity domains of the nucleocapsid protein of SARS-CoV-2 form amyloid fibrils
Here, the authors show the amyloid formation of a low-complexity domain of NCAP, and its potential for guiding the design of antiviral agents.
- Einav Tayeb-Fligelman
- , Jeannette T. Bowler
- & David S. Eisenberg
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Article
| Open AccessRPL3L-containing ribosomes determine translation elongation dynamics required for cardiac function
RPL3L is a paralog of the ribosomal protein RPL3 and specifically expressed in heart and skeletal muscle. Here, the authors show that RPL3L-containing ribosomes regulate translation elongation dynamics especially for the transcripts related to cardiac muscle contraction.
- Chisa Shiraishi
- , Akinobu Matsumoto
- & Keiichi I. Nakayama
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Article
| Open AccessPeSTo: parameter-free geometric deep learning for accurate prediction of protein binding interfaces
Predicting protein interactions is crucial for understanding biological functions. Here, authors introduce a geometric transformer that accurately identifies protein binding interfaces, enabling new insights into unexplored biology.
- Lucien F. Krapp
- , Luciano A. Abriata
- & Matteo Dal Peraro
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Article
| Open AccessHsp90 provides a platform for kinase dephosphorylation by PP5
PP5 requires the molecular chaperone Hsp90 to dephosphorylate CRaf kinase and the Hsp90 cochaperone Cdc37. Here, authors show how Hsp90 acts as a platform to allow for targeted dephosphorylation by PP5.
- Maru Jaime-Garza
- , Carlos A. Nowotny
- & David A. Agard
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Article
| Open AccessStructure and mechanism of the alkane-oxidizing enzyme AlkB
Alkane monooxygenase (AlkB) plays a key role in the global carbon cycle and remediation of oil spills. Here, the authors report the cryo-EM structure of AlkB to provide insight into the catalytic mechanism and substrate selectivity.
- Xue Guo
- , Jianxiu Zhang
- & Liang Feng
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Article
| Open AccessControlling protein stability with SULI, a highly sensitive tag for stabilization upon light induction
Tools for the spatiotemporal control of protein abundance are valuable in studying diverse complex biological processes. Here, authors engineered a protein tag which is stabilized upon light induction but which quickly degrades the protein of interest in the dark, demonstrating control of protein stability in yeast and zebrafish.
- Miaowei Mao
- , Yajie Qian
- & Yi Yang
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Article
| Open AccessSynDLP is a dynamin-like protein of Synechocystis sp. PCC 6803 with eukaryotic features
In eukaryotes, dynamins and dynamin-like proteins (DLPs) are involved in various membrane remodeling processes. Here, the authors present the structure and functional characterization of a DLP of the cyanobacterium Synechocystis sp. PCC 6803.
- Lucas Gewehr
- , Benedikt Junglas
- & Dirk Schneider
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Article
| Open AccessConstrained catecholamines gain β2AR selectivity through allosteric effects on pocket dynamics
Constrained catecholamines gain β2AR selectivity. Although the orthosteric pockets are identical in β1AR and β2AR, surrounding residues allosterically modify the pockets and contribute to the β2AR selectivity of the constrained catecholamines.
- Xinyu Xu
- , Jeremy Shonberg
- & Peter Gmeiner
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Comment
| Open AccessStructural insights into how augmin augments the mitotic spindle
Cell division critically requires amplification of microtubules (MTs) in the bipolar mitotic spindle. This relies on the filamentous augmin complex that enables MT branching. Studies by Gabel et al., Zupa et al. and Travis et al. describe consistent integrated atomic models of the extraordinarily flexible augmin complex. Their work prompts the question: what is this flexibility really needed for?
- Szymon W. Manka
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Article
| Open AccessIntegrated model of the vertebrate augmin complex
Many microtubules in the mitotic spindle are made through microtubule branching. Here, the authors report a structural model of the augmin complex and insights into its role in microtubule branching.
- Sophie M. Travis
- , Brian P. Mahon
- & Sabine Petry
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Article
| Open AccessThe RNA-binding protein landscapes differ between mammalian organs and cultured cells
Characterization of RNA-binding proteins (RBPs) in tissues has been hampered by technical constraints. Here, the authors describe ex vivo eRIC, a method for global profiling of RBPs active in mammalian organs, and report comprehensive RBP atlases from mouse brain, kidney and liver.
- Joel I. Perez-Perri
- , Dunja Ferring-Appel
- & Matthias W. Hentze
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Article
| Open AccessCryo-EM structures of mitochondrial ABC transporter ABCB10 in apo and biliverdin-bound form
ABCB10 is a mitochondrial biliverdin exporter. Here, authors report the cryo-EM structures of ABCB10 apo and biliverdin-bound forms, revealing a cholesterol binding site that promotes the ATPase activity and thermostability of ABCB10.
- Sheng Cao
- , Yihu Yang
- & Zhuqing Ouyang
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Article
| Open AccessA cationic motif upstream Engrailed2 homeodomain controls cell internalization through selective interaction with heparan sulfates
Here, the authors show that cell internalization of Engrailed2 not only relies on its homeodomain, but also involves a cationic region which interacts selectively with cell surface heparan sulfates.
- Sébastien Cardon
- , Yadira P. Hervis
- & Sandrine Sagan
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Article
| Open AccessConformational cycle of human polyamine transporter ATP13A2
ATP13A2 is a lysosomal polyamine transporter, mutated in several diseases including juvenile-onset Parkinson’s disease. Here, the authors report structures of human ATP13A2 in six distinct intermediate states, illustrating most of its conformational cycle.
- Jianqiang Mu
- , Chenyang Xue
- & Zhongmin Liu
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Article
| Open AccessTargeting USP2 regulation of VPRBP-mediated degradation of p53 and PD-L1 for cancer therapy
The clinical success of restoring P53 for cancer therapy has been limited due to toxicity. Here, the authors identify USP2 as an upstream regulator of VPRBP-mediated degradation of p53 and PD-L1 and demonstrate the efficacy of combining USP2 inhibitor and PD-L1/PD-1 immune checkpoint blockade in cancers.
- Jingjie Yi
- , Omid Tavana
- & Wei Gu
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