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| Open AccessStructural basis of the molecular ruler mechanism of a bacterial glycosyltransferase
The glycosyltransferase PglH transfers three terminal N-acetylgalactosamine (GalNAc) residues to a carrier, which is a prerequisite for bacterial protein N-glycosylation. Here authors present the crystal structures of PglH in three distinct states and show that a ‘ruler helix’ facilitates membrane attachment and glycan counting.
- Ana S. Ramírez
- , Jérémy Boilevin
- & Kaspar P. Locher
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Article
| Open AccessType IX secretion system PorM and gliding machinery GldM form arches spanning the periplasmic space
No structural data for the bacterial type IX secretion system (T9SS) are available so far. Here, the authors present the crystal structures of the periplasmic domains from two major T9SS components PorM and GldM, which span most of the periplasmic space, and propose a putative model of the T9SS core membrane complex.
- Philippe Leone
- , Jennifer Roche
- & Alain Roussel
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Article
| Open AccessStructure of tick-borne encephalitis virus and its neutralization by a monoclonal antibody
The tick-borne encephalitis virus (TBEV) causes thousands of cases of meningitis and encephalitis annually. Here, the authors describe a cryo-EM structure of the TBEV virion bound by Fab fragments of the neutralizing antibody 19/1786, revealing a mechanism whereby this antibody prevents virus membrane fusion.
- Tibor Füzik
- , Petra Formanová
- & Pavel Plevka
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Article
| Open AccessMolecular basis for the specific and multivariant recognitions of RNA substrates by human hnRNP A2/B1
RNA-binding protein hnRNP A2/B1 is suggested to promote miRNA processing as a m6A 'reader'. Here, the authors determine crystal structures of RRM domains of hnRNP A2/B1 in complex with various RNA substrates and determine that hnRNP A2/B1 may function as an auxiliary factor in 'm6A switch' instead.
- Baixing Wu
- , Shichen Su
- & Jinbiao Ma
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Article
| Open AccessThe SAM domain of mouse SAMHD1 is critical for its activation and regulation
The sterile alpha-motif and histidine-aspartate domain-containing protein 1 (SAMHD1) is a dNTP phosphohydrolase that blocks HIV-1 infection by depleting cellular dNTPs. Here the authors present the structures of full-length mouse SAMHD1 in different nucleotide bound states and give insights into SAMHD1 activity regulation.
- Olga Buzovetsky
- , Chenxiang Tang
- & Yong Xiong
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Article
| Open AccessStructural insight into molecular mechanism of poly(ethylene terephthalate) degradation
Poly(ethylene terephthalate) (PET) is a widely used plastic and its accumulation in the environment has become global problem. Here the authors report the crystal structure of a Ideonella sakaiensis PET-degrading enzyme and propose a molecular mechanism for PET degradation.
- Seongjoon Joo
- , In Jin Cho
- & Kyung-Jin Kim
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Article
| Open AccessA dual role for the N-terminal domain of the IL-3 receptor in cell signalling
The N-terminal domain (NTD) of interleukin-3 receptor α-subunit (IL3Rα) is involved in IL-3 recognition but the underlying mechanism is unknown. Here, the authors present crystal structures of the IL3Rα complex and provide biochemical evidence that the NTD regulates IL-3 binding and signalling complex assembly.
- Sophie E. Broughton
- , Timothy R. Hercus
- & Michael W. Parker
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Article
| Open AccessMolecular snapshots of APE1 proofreading mismatches and removing DNA damage
The essential DNA repair enzyme apurinic/apyrimidinic endonuclease 1 (APE1) has both endonuclease and exonuclease activities. Here, the authors present DNA bound human APE1 crystal structures which give insights into its exonuclease mechanism.
- Amy M. Whitaker
- , Tony S. Flynn
- & Bret D. Freudenthal
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Article
| Open AccessAutomated NMR resonance assignments and structure determination using a minimal set of 4D spectra
Further automation of NMR structure determination is needed to increase the throughput and accessibility of this method. Here the authors present 4D-CHAINS/autoNOE-Rosetta, a complete pipeline that allows rapid and fully automated structure determination from two highly complementary NMR datasets.
- Thomas Evangelidis
- , Santrupti Nerli
- & Konstantinos Tripsianes
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Article
| Open AccessCrystal structure of lipid A disaccharide synthase LpxB from Escherichia coli
LpxB is a membrane-associated glycosyltransferase required for bacterial lipopolysaccharide biosynthesis. Here, Bohl et al. solve the crystal structure of a soluble LpxB variant, showing an intertwined C-terminally swapped dimer, and residues likely mediating association with lipidic substrates or the membrane.
- Heather O. Bohl
- , Ke Shi
- & Hideki Aihara
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Article
| Open AccessShielding and activation of a viral membrane fusion protein
Viral fusion proteins undergo extensive conformational changes during entry but intermediate conformations often remain unknown. Here, the authors show how Gn of Rift Valley fever virus fusion protein shields hydrophobic fusion loops of Gc and how these loops embed in the target membrane at acidic conditions.
- Steinar Halldorsson
- , Sai Li
- & Juha T. Huiskonen
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Article
| Open AccessMixed pyruvate labeling enables backbone resonance assignment of large proteins using a single experiment
Structure determination of large proteins by solution state NMR is challenging due to spectral overlap. Here the authors present a labeling strategy using 2-13C and 3-13C pyruvate as carbon source for E. coli, which increases the effective resolution of triple-resonance HNCA experiments and helps to overcome this problem.
- Scott A. Robson
- , Koh Takeuchi
- & Haribabu Arthanari
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Article
| Open AccessEpsin and Sla2 form assemblies through phospholipid interfaces
Adapter proteins assist clathrin coated pit assembly. Here, the authors combine native mass spectrometry, crystallography and SAXS measurements and show that the membrane–proximal domains of the adaptor proteins epsin and Sla2 form complexes mediated through phosphatidylinositol 4,5-bisphosphate interfaces leading to assembly formation.
- Maria M. Garcia-Alai
- , Johannes Heidemann
- & Rob Meijers
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Article
| Open AccessStructural basis of SALM5-induced PTPδ dimerization for synaptic differentiation
Synaptic adhesion molecules mediate synaptic differentiation and formation. Here the authors present the structures of the synaptic adhesion molecule SALM5 alone and in complex with the LAR family receptor protein tyrosine phosphatase (LAR-RPTP) PTPδ, which reveals how SALM5 dimerization facilitates higher-order signaling assembly of LAR-RPTPs.
- Zhaohan Lin
- , Jianmei Liu
- & Heli Liu
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Article
| Open AccessCrystal structure of an assembly intermediate of respiratory Complex II
The mechanism for covalent flavinylation of flavoenzymes is still unclear. Here, the authors propose a mechanism based on the crystal structure of a flavinylation assembly intermediate of the E. coli respiratory Complex II comprising the E. coli FrdA subunit bound to covalent FAD and crosslinked with its assembly factor SdhE.
- Pankaj Sharma
- , Elena Maklashina
- & T. M. Iverson
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Article
| Open AccessStructural basis of trans-synaptic interactions between PTPδ and SALMs for inducing synapse formation
Synaptic organizers are cell adhesion molecules that facilitate synapse formation through trans-synaptic interactions. Here the authors give molecular insights into synaptic differentiation by determining the structures of the synaptic adhesion-like molecules SALM2 and SALM5 bound to the presynaptic organizer PTPδ.
- Sakurako Goto-Ito
- , Atsushi Yamagata
- & Shuya Fukai
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Article
| Open AccessPhosphorylation induced cochaperone unfolding promotes kinase recruitment and client class-specific Hsp90 phosphorylation
The Hsp90 chaperone cycle is influenced by multiple phosphorylation events but their regulatory functions are poorly understood. Here, the authors show that phosphorylation and unfolding of cochaperone Cdc37 tailors the Hsp90 chaperone cycle by recruiting kinases that promote distinct phosphorylation patterns.
- Ashleigh B. Bachman
- , Dimitra Keramisanou
- & Ioannis Gelis
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Article
| Open AccessStructural basis for chitin acquisition by marine Vibrio species
Chitin degrading bacteria are important for marine ecosystems. Here the authors structurally and functionally characterize the Vibrio harveyi outer membrane diffusion channel chitoporin and give mechanistic insights into chito-oligosaccharide uptake.
- Anuwat Aunkham
- , Michael Zahn
- & Bert van den Berg
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Article
| Open AccessPhosphorylation-induced conformation of β2-adrenoceptor related to arrestin recruitment revealed by NMR
Upon stimulation by agonist binding, the C-terminal regions of G-protein-coupled receptors (GPCRs) become phosphorylated by GPCR kinases, and phosphorylated GPCRs bind arrestin. Here the authors give structural insights into the phosphorylation induced conformational changes in GPCRs by performing NMR studies with the β2-adrenoceptor.
- Yutaro Shiraishi
- , Mei Natsume
- & Ichio Shimada
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Article
| Open AccessStructure of a MacAB-like efflux pump from Streptococcus pneumoniae
Bacterial ATP-binding cassette (ABC)-type efflux pumps are involved in the resistance of antibiotics and antimicrobial peptides. Here authors report the crystal structures and ATPase activity of the MacAB-like efflux pump from Streptococcus pneumonia and describe a putative substrate transport mechanism.
- Hong-Bo Yang
- , Wen-Tao Hou
- & Cong-Zhao Zhou
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Article
| Open AccessDisulfide isomerization reactions in titin immunoglobulin domains enable a mode of protein elasticity
Titin regulates myocyte stiffness through uncoiling and unfolding but these two processes cannot fully explain its elasticity. Here, the authors use atomic force microscopy to study the properties of titin disulfide bonds, showing that disulfide isomerization represents a third mode of titin elasticity.
- David Giganti
- , Kevin Yan
- & Jorge Alegre-Cebollada
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Article
| Open AccessStructural insights into two distinct binding modules for Lys63-linked polyubiquitin chains in RNF168
E3 ubiquitin ligase RNF168 is important for the repair of DNA double-strand breaks and recognizes ubiquitylated targets through two Ub-dependent DSB recruitment modules UDM1 and UDM2. Here the authors combine crystallography, cell biology and biochemical experiments to reveal how UDM1 and UDM2 interact with polyubiquitin chains.
- Tomio S. Takahashi
- , Yoshihiro Hirade
- & Shuya Fukai
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Article
| Open AccessSignaling ammonium across membranes through an ammonium sensor histidine kinase
For anammox bacteria, the sensing and uptake of ammonium is essential and specialized proteins, like Ks-Amt5, mediate such processes. Here, authors perform biophysical, biochemical, and structural analysis on Ks-Amt5 and establish a role for this protein as an ammonium-sensing signal transducer.
- Tobias Pflüger
- , Camila F. Hernández
- & Susana L. A. Andrade
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Article
| Open AccessThe mechanism of glycosphingolipid degradation revealed by a GALC-SapA complex structure
Lysosomal degradation of sphingolipids requires lipid-binding saposin proteins and hydrolytic enzymes. Here the authors present the crystal structure of the hydrolase β-galactocerebrosidase in complex with saposin SapA and give insights into the glycosphingolipid galactocerebroside degradation mechanism.
- Chris H. Hill
- , Georgia M. Cook
- & Janet E. Deane
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Article
| Open AccessThe peroxisomal AAA-ATPase Pex1/Pex6 unfolds substrates by processive threading
Pex1 and Pex6 form a heterohexameric Type-2 AAA-ATPase motor whose function in peroxisomal matrix-protein import is still debated. Here, the authors combine structural, biochemical, and cell-biological approaches to show that Pex1/Pex6 is a protein unfoldase, which supports a role in mechanical unfolding of peroxin proteins.
- Brooke M. Gardner
- , Dominic T. Castanzo
- & Andreas Martin
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Article
| Open AccessThe evolution of substrate discrimination in macrolide antibiotic resistance enzymes
New antibiotics with reduced potential for resistance are urgently needed. Here, the authors use a multidisciplinary approach to characterize substrate discrimination in macrolide resistance kinases and present a strategy for the prediction of mutations that expand the substrate range of antibiotic-inactivating enzymes.
- Andrew C. Pawlowski
- , Peter J. Stogios
- & Gerard D. Wright
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Article
| Open AccessMechanism and structural diversity of exoribonuclease-resistant RNA structures in flaviviral RNAs
Subgenomic flavivirus RNAs are generated by a host exoribonuclease and play an important role in virus replication and pathogenesis. Here, the authors show the mechanism by which subgenomic flavivirus RNAs are generated and identify two structurally distinct sfRNA classes in flaviviruses.
- Andrea MacFadden
- , Zoe O’Donoghue
- & Jeffrey S. Kieft
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Article
| Open AccessStructure function and engineering of multifunctional non-heme iron dependent oxygenases in fungal meroterpenoid biosynthesis
Non-heme iron and α-ketoglutarate (αKG) oxygenases play a major role in fungal meroterpenoid biosynthesis, but their mechanism remains elusive. Here the authors present crystal structures of two oxygenases, AusE and PrhA, which provide insights into the multifunctional nature of these enzymes.
- Yu Nakashima
- , Takahiro Mori
- & Ikuro Abe
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Article
| Open AccessStructural analysis of mtEXO mitochondrial RNA degradosome reveals tight coupling of nuclease and helicase components
The mitochondrial RNA degradosome (mtEXO) plays an essential role in the regulation of mitochondrial gene expression and is composed of the 3′-to-5′ exoribonuclease Dss1 and the helicase Suv3. Here the authors present the RNA bound mtEXO crystal structure and give insights into its mechanism.
- Michal Razew
- , Zbigniew Warkocki
- & Marcin Nowotny
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Article
| Open AccessMechanistic insights into the role of prenyl-binding protein PrBP/δ in membrane dissociation of phosphodiesterase 6
The prenyl-binding protein PrBP/δ is a solubilization factor involved in trafficking of prenylated proteins. Here the authors present the ligand-free apo-PrBP/δ structure and propose a "solubilization by depletion" mechanism, where PrBP/δ sequesters only soluble rod photoreceptor phosphodiesterase (PDE6), leading to a dissociation of membrane-bound PDE6.
- Bilal M. Qureshi
- , Andrea Schmidt
- & Patrick Scheerer
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Article
| Open AccessCryo EM structure of intact rotary H+-ATPase/synthase from Thermus thermophilus
H+-ATPases employ a rotary catalytic mechanism to couple ATP synthesis/hydrolysis with proton translocation through the membrane. Here, the authors use high-resolution cryoEM to characterize three rotational states of a bacterial H+-ATPase, providing a more detailed model of its catalytic mechanism.
- Atsuko Nakanishi
- , Jun-ichi Kishikawa
- & Ken Yokoyama
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Article
| Open AccessImportance of the 1+7 configuration of ribonucleoprotein complexes for influenza A virus genome packaging
Influenza A virus (IAV) packages its eight genomic RNA segments in a specific “1+7” pattern. Here, the authors generate IAV that lack one RNA segment and show that ribosomal RNA is packaged in place of the eighth segment, suggesting that the 1+7 pattern is important for particle production.
- Takeshi Noda
- , Shin Murakami
- & Yoshihiro Kawaoka
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Article
| Open AccessThe protease GtgE from Salmonella exclusively targets inactive Rab GTPases
The bacterial protease GtgE is involved in the establishment of Salmonellosis. Here the authors provide a structural and biochemical analysis of GtgE that sheds light on the molecular mechanisms of reprogramming infected host cells via site-specific proteolytic cleavage of the vesicular trafficking regulator Rab32.
- Rudolf Wachtel
- , Bastian Bräuning
- & Aymelt Itzen
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Article
| Open AccessStructural basis for DNA 3′-end processing by human tyrosyl-DNA phosphodiesterase 1
Human tyrosyl-DNA phosphodiesterase 1 (Tdp1) repairs covalently trapped topoisomerase 1B-DNA complexes and other lesions, and is a target for anticancer drug development. Here the authors use an integrated structural approach to shed light onto the molecular basis of DNA end-processing by Tdp1.
- Fiona J. Flett
- , Emilija Ruksenaite
- & Julia M. Richardson
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Article
| Open AccessStructural characterisation reveals insights into substrate recognition by the glutamine transporter ASCT2/SLC1A5
Cancer cells are reliant on nutrients such as glutamine, which enter the cell via the alanine/serine/cysteine transporter 2 (ASCT2). Here, authors use crystallography to show which amino-acid residues in the substrate-binding site are responsible for conferring glutamine selectivity to ASCT2.
- Amanda J Scopelliti
- , Josep Font
- & Renae M Ryan
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Article
| Open AccessVAMPnets for deep learning of molecular kinetics
Extracting kinetic models from high-throughput molecular dynamics (MD) simulations is laborious and prone to human error. Here the authors introduce a deep learning framework that automates construction of Markov state models from MD simulation data.
- Andreas Mardt
- , Luca Pasquali
- & Frank Noé
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Article
| Open AccessMethylation-regulated decommissioning of multimeric PP2A complexes
Protein phosphatase 2A (PP2A) forms different holoenzymes but little is known about the disassembly of these important signalling complexes. Here the authors present the crystal structure of PP2A bound to TOR signaling pathway regulator (TIPRL) and give insights into the methylation-dependent disassembly of PP2A holenzymes.
- Cheng-Guo Wu
- , Aiping Zheng
- & Yongna Xing
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Article
| Open AccessStructure of a Wbl protein and implications for NO sensing by M. tuberculosis
Mycobacterium tuberculosis WhiB1 is a DNA-binding protein with a NO sensitive [4Fe-4S] cluster. Here the authors present the NMR structure of WhiB1 and suggest how loss of the iron-sulfur cluster through nitrosylation affects WhiB1 DNA binding and leads to transcriptional reprogramming.
- Bassam K. Kudhair
- , Andrea M. Hounslow
- & Jeffrey Green
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Article
| Open AccessDouble mimicry evades tRNA synthetase editing by toxic vegetable-sourced non-proteinogenic amino acid
Non-proteinogenic (np) amino acids in the food chain present challenges for the human translation machinery. Here the authors show that, while AlaRS and ProRS activate toxic np azetidine-2-carboxylic acid (Aze) present in sugar beets and lilies, only the AlaRS editing system rejects Aze.
- Youngzee Song
- , Huihao Zhou
- & Paul Schimmel
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Article
| Open AccessThe mechanism of NDM-1-catalyzed carbapenem hydrolysis is distinct from that of penicillin or cephalosporin hydrolysis
New Delhi metallo-β-lactamases (NDMs) hydrolyze almost all β-lactam antibiotics and pose a major public health threat. Here, the authors study the mechanism of NDM-1 catalyzed carbapenem hydrolysis and present the crystal structures of the enzyme-intermediate and product complexes, which is important for drug design.
- Han Feng
- , Xuehui Liu
- & Wei Liu
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Article
| Open AccessCryo-EM structure of a licensed DNA replication origin
Origins of replication are licensed by loading of MCM onto DNA, and origin firing depends on interaction with Cdc45 and GINS to form two CMG holo-helicases. Here, authors determine the cryo-EM structures of DNA-bound MCM and visualise a phospho-dependent MCM element important for Cdc45 recruitment.
- Ferdos Abid Ali
- , Max E. Douglas
- & Alessandro Costa
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Article
| Open AccessDynamic intramolecular regulation of the histone chaperone nucleoplasmin controls histone binding and release
The histone chaperone nucleoplasmin (Npm) stores histones H2A/H2B in the egg and embryo. Here, the authors use NMR to show that Npm’s intrinsically disordered tail domain controls histone binding at an acidic stretch, which is autoregulated through direct competition with its basic C-terminus.
- Christopher Warren
- , Tsutomu Matsui
- & David Shechter
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Article
| Open AccessA hydrophobic anchor mechanism defines a deacetylase family that suppresses host response against YopJ effectors
A subset of α/β hydrolases is known to suppress the pathogen-triggered hypersensitive response (HR) in plants, but their mechanism of action remains unclear. The authors present two crystal structures and functional analyses of these enzymes, showing that HR is suppressed by a previously unknown family of deacetylases.
- Marco Bürger
- , Björn C. Willige
- & Joanne Chory
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Article
| Open AccessUnravelling the specificity and mechanism of sialic acid recognition by the gut symbiont Ruminococcus gnavus
The mucus layer is an important physical niche within the gut which harbours a distinct microbial community. Here the authors show that specific carbohydrate-binding modules associated with bacterial carbohydrate-active enzymes are mucus adhesins that target regions of the distal colon rich in sialomucins.
- C. David Owen
- , Louise E. Tailford
- & Nathalie Juge
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Article
| Open AccessAllosteric modulation of protein-protein interactions by individual lipid binding events
Native mass spectrometry (MS) is a technique that preserves non-covalent interactions in the mass spectrometer. Here the authors use native MS to study integral membrane proteins, and find that lipids with different headgroups and tails can allosterically modulate protein-protein interactions in different fashions.
- Xiao Cong
- , Yang Liu
- & Arthur Laganowsky
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Article
| Open AccessCatastrophic disassembly of actin filaments via Mical-mediated oxidation
MICAL Redox enzymes post-translationally modify F-actin to promote its cellular destabilization. Here, the authors present a 3.9Å cryoEM structure of Mical-oxidized F-actin, showing its nucleotide-state dependent dynamic instability and susceptibility to cofilin-induced severing in the presence of inorganic phosphate.
- Elena E. Grintsevich
- , Peng Ge
- & Emil Reisler
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Article
| Open AccessEvolutionary action and structural basis of the allosteric switch controlling β2AR functional selectivity
Ligand-induced biased signaling is thought to result in part from ligand-specific receptor conformations that cause the engagement of distinct effectors. Here the authors trace and evaluate the impact of mutations of the β2–adrenergic receptor on multiple signaling outputs to provide structural-level insight into the determinants of GPCR functional selectivity.
- Anne-Marie Schönegge
- , Jonathan Gallion
- & Michel Bouvier
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Article
| Open AccessSurvey of solution dynamics in Src kinase reveals allosteric cross talk between the ligand binding and regulatory sites
Src is a prototypical signaling non-receptor protein tyrosine kinase that interconverts between distinct conformations. Here the authors use variants of the kinase-inhibitor dasatinib to define three specific conformational states of the Src kinase and shed insight on the effect of conformation-specific inhibitors on Src dynamics.
- Michael Tong
- , Jeff G. Pelton
- & Markus A. Seeliger
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Article
| Open AccessStructural and functional dissection of the DH and PH domains of oncogenic Bcr-Abl tyrosine kinase
The Bcr-Abl tyrosine kinases p210 and p190 are linked to different leukemias and differ by the Dbl homology (DH) and Pleckstrin-homology (PH) domains. Here the authors characterize structures of the Bcr-Abl p210 DH and PH domains and find that the PH domain is important for the cellular localization and signaling network of p210.
- Sina Reckel
- , Charlotte Gehin
- & Oliver Hantschel