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| Open AccessIlluminating the mechanism and allosteric behavior of NanoLuc luciferase
NanoLuc luciferase is a popular bioluminescent enzyme, but the molecular details of its mechanism of action on luciferins such as coelenterazine remained elusive. Here the authors use, protein crystal structures and biochemical analyses to provide an atomistic description of its catalytic mechanism and allosteric behaviour.
- Michal Nemergut
- , Daniel Pluskal
- & Martin Marek
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Article
| Open AccessUnexpected dynamics in femtomolar complexes of binding proteins with peptides
High binding affinities are usually obtained when ligands are rigidified. Here the authors present flexible peptides binding to Armadillo repeat proteins with femtomolar affinity. They demonstrate that the bound state is characterized by residual dynamics limiting entropic losses upon binding.
- Stefano Cucuzza
- , Malgorzata Sitnik
- & Oliver Zerbe
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Article
| Open AccessStructural and functional insights into the delivery of a bacterial Rhs pore-forming toxin to the membrane
Bacterial Rhs proteins constitute a diverse family of secreted toxins. Here, the authors present a cryo-electron microscopy structure of an Rhs protein from Pseudomonas aeruginosa and provide insights into the mechanisms by which the protein delivers its encapsulated pore-forming toxin fragment to the bacterial membrane.
- Amaia González-Magaña
- , Igor Tascón
- & David Albesa-Jové
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Article
| Open AccessLipIDens: simulation assisted interpretation of lipid densities in cryo-EM structures of membrane proteins
Interpretation of lipid-like densities in cryo-EM structures of membrane proteins is challenging. Here authors present LipIDens, enabling molecular dynamics analysis of protein-lipid interactions.
- T. Bertie Ansell
- , Wanling Song
- & Mark S. P. Sansom
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Article
| Open AccessMolecular basis for the catalytic mechanism of human neutral sphingomyelinases 1 (hSMPD2)
Neutral sphingomyelinases play pivotal roles in ceramide-related signaling transduction. Here, the authors solve the structure of human neutral sphingomyelinase SMPD2 and propose a catalytic mechanism, potentially enhancing understanding of ceramide in disease and cancer treatment.
- Jingbo Yi
- , Boya Qi
- & Maojun Yang
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Article
| Open AccessDiscovery of a non-canonical prototype long-chain monoacylglycerol lipase through a structure-based endogenous reaction intermediate complex
Here, the authors present the structure of an orphan lipase in complex with an endogenous C18 monoacylglycerol ester reaction intermediate derived from the expression host, which along with enzymatic assays enabled functional assignment as a prototypical long-chain monoacylglycerol lipase.
- Nikos Pinotsis
- , Anna Krüger
- & Matthias Wilmanns
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Article
| Open AccessStochastic chain termination in bacterial pilus assembly
Adhesive type-1 pili from Escherichia coli are filamentous protein complexes consisting of a short tip and a long rod formed by up to several thousand copies of a major subunit. Here, Giese et al. reconstitute the entire type-1 pilus rod assembly reaction in vitro, using all constituent protein subunits, and identify a subunit that acts as an irreversible assembly terminator.
- Christoph Giese
- , Chasper Puorger
- & Rudi Glockshuber
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Article
| Open AccessCommon transthyretin-derived amyloid fibril structures in patients with hereditary ATTR amyloidosis
Hereditary ATTR amyloidosis has diverse disease manifestations. Using cryo-EM it was possible to reveal, that the phenotypic variations arise from the circumstances under which the amyloid fibrils are formed, rather than from different fibril morphologies.
- Maximilian Steinebrei
- , Julian Baur
- & Marcus Fändrich
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Article
| Open AccessStructure of the DDB1-AMBRA1 E3 ligase receptor complex linked to cell cycle regulation
AMBRA1 functions as a substrate receptor for E3 ubiquitin ligase complexes to promote ubiquitination and degradation of Cyclin D. Here the authors demonstrated the structure of AMRBA1 in complex with DDB1. Disruption of intermolecular interactions caused deregulation of cell cycle and DNA damage repair.
- Ming Liu
- , Yang Wang
- & Goran Stjepanovic
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Article
| Open AccessOrthosteric and allosteric modulation of human HCAR2 signaling complex
Hydroxycarboxylic acid receptor 2 (HCAR2) has been implicated in cardiovascular and neuroinflammatory diseases. Here, the authors present cryo-EM structures of HCAR2-Gi1 complexes bound to different ligands and provide insights into the mechanisms of both orthosteric and allosteric modulation of HCAR2.
- Chunyou Mao
- , Mengru Gao
- & Yan Zhang
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Article
| Open AccessStructure of the N-RNA/P interface indicates mode of L/P recruitment to the nucleocapsid of human metapneumovirus
To read and transcribe the viral genome, the polymerase complex of human metapneumovirus (HMPV) needs to attach to the nucleocapsid. Here, the authors define the dynamic basis of how the polymerase cofactor P facilitates this attachment.
- Jack D. Whitehead
- , Hortense Decool
- & Max Renner
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Article
| Open AccessMyr-Arf1 conformational flexibility at the membrane surface sheds light on the interactions with ArfGAP ASAP1
An integrated approach combing solution and solid-state NMR, molecular dynamics simulations and neutron reflectometry is applied to characterize dynamic membrane bound forms of ADP-ribosylation factor 1 (Arf1).
- Yue Zhang
- , Olivier Soubias
- & R. Andrew Byrd
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Article
| Open AccessStructure-based discovery of dual pathway inhibitors for SARS-CoV-2 entry
TMPRSS2 and CTSL/CTSB, host proteases that facilitate SARS-CoV-2 entry, are promising drug targets. Here the authors simultaneously inhibit these host proteases and see synergistic antiviral effects, offering a broad-spectrum intervention against SARS-CoV-2 variants.
- Haofeng Wang
- , Qi Yang
- & Haitao Yang
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Article
| Open AccessThe structure of the teleost Immunoglobulin M core provides insights on polymeric antibody evolution, assembly, and function
The formation of polymeric Ig complexes is important for the function of IgM and can vary between species. Here the authors structurally analyse IgM from a teleost species that doesn’t encode a joining chain, which results in a different 3D structure compared to mammalian IgM where other parts of the protein associate to form polymeric complexes.
- Mengfan Lyu
- , Andrey G. Malyutin
- & Beth M. Stadtmueller
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Article
| Open AccessStructures of the interleukin 11 signalling complex reveal gp130 dynamics and the inhibitory mechanism of a cytokine variant
Interleukin (IL-)11 is a signaling protein that plays key roles in several human diseases. Here the authors describe structures of IL-11 in complex with its receptors and determine the molecular mechanisms through which a variant of IL-11 inhibits signalling, opening avenues for therapeutic development.
- Riley D. Metcalfe
- , Eric Hanssen
- & Michael D. W. Griffin
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Article
| Open AccessArchitecture and regulation of a GDNF-GFRα1 synaptic adhesion assembly
The soluble neurotrophic factor GDNF promotes trans-synaptic adhesion through its co-receptor GFRα1. Here, the authors describe the structural basis for GDNF-GFRα1 adhesion and reconstitute assemblies bridging membranes, demonstrating that binding of either the RET receptor or proteoglycans can disrupt this adhesive function.
- F. M. Houghton
- , S. E. Adams
- & N. Q. McDonald
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Article
| Open AccessMembrane potential accelerates sugar uptake by stabilizing the outward facing conformation of the Na/glucose symporter vSGLT
Sodium glucose transporters are critical for maintaining glucose homeostasis. Here, authors provide a detailed framework for how SGLTs utilize cellular membrane potentials to stabilize their substrate accepting conformation leading to accelerated transport.
- Farha Khan
- , Matthias Elgeti
- & Jeff Abramson
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Article
| Open AccessArchitecture of the baculovirus nucleocapsid revealed by cryo-EM
Baculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV) is used as a bioinsecticide and a protein expression vector. Here, the authors report structures of cylindrical body of the AcMNPV nucleocapsid, as well as of both the nucleocapsid head and base.
- Xudong Jia
- , Yuanzhu Gao
- & Qinfen Zhang
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Article
| Open AccessActivation and substrate specificity of the human P4-ATPase ATP8B1
Asymmetric phospholipid distribution in cell membranes is vital for cellular function. Here, authors reveal how ATP8B1, a P4-ATPase, can transport different lipids, including phosphatidylinositol.
- Thibaud Dieudonné
- , Felix Kümmerer
- & Poul Nissen
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Article
| Open AccessSerine peptidase Vpr forms enzymatically active fibrils outside Bacillus bacteria revealed by cryo-EM
Here, cryo-EM is used to identify an unreported fibril species derived from lab-cultured Bacillus amyloiquefaciens composed of the extracellular serine peptidase Vpr. Fibrillar Vpr is shown to be enzymatically active, suggesting the fibril form represents a strategy of enriching Vpr extracellular activity.
- Yijia Cheng
- , Jianting Han
- & Qin Cao
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Article
| Open AccessA tradeoff between enterovirus A71 particle stability and cell entry
Viruses are thought to have evolved an optimal equilibrium between particle stability and efficiency of cell entry. Here, the authors show that a single mutation in enterovirus A71 capsid affects the balance between particle stability and cell entry efficiency. Structural and simulation analyses reveal an expanded conformation in the thermostable viruses, resulting in increased particle flexibility.
- Adam Catching
- , Ming Te Yeh
- & Raul Andino
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Article
| Open AccessUnconventional structure and mechanisms for membrane interaction and translocation of the NF-κB-targeting toxin AIP56
Structural and functional characterization of an NF-κB-targeting bacterial toxin reveals an unconventional structure and mechanisms of membrane interaction and translocation.
- Johnny Lisboa
- , Cassilda Pereira
- & Nuno M. S. dos Santos
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Article
| Open AccessProRefiner: an entropy-based refining strategy for inverse protein folding with global graph attention
Inverse Protein Folding is a critical component of protein design. Here, authors introduce ProRefiner, a deep-learning model for IPF that exhibits both high performance and memory efficiency, thereby contributing to advancements in protein design.
- Xinyi Zhou
- , Guangyong Chen
- & Pheng Ann Heng
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Article
| Open AccessThe structural and functional investigation into an unusual nitrile synthase
The nitrile synthase AetD is a crucial component in the biosynthetic pathway of neurotoxin aetokthonotoxin (AETX). Here, the authors solved crystal structures of AetD in complex with different substrates, revealing that AetD represents a new type of HO-like diiron enzyme and the possibility of expanding its substrate spectrum.
- Hao Li
- , Jian-Wen Huang
- & Chun-Chi Chen
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Article
| Open AccessStructural and dynamic mechanisms for coupled folding and tRNA recognition of a translational T-box riboswitch
T-box riboswitches are RNA-based gene regulators, composed of highly structured noncoding RNAs: the T-box and a tRNA ligand. Here, the authors assess the folding of a translational T-box aptamer and dissect the role of Mg2+, intra- and intermolecular RNA-RNA interactions in modulating its folding and function.
- Xiaolin Niu
- , Zhonghe Xu
- & Xianyang Fang
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Article
| Open AccessM. mazei glutamine synthetase and glutamine synthetase-GlnK1 structures reveal enzyme regulation by oligomer modulation
Glutamine synthetases (GS) play vital roles in cellular nitrogen assimilation and hence these enzymes, which form large oligomeric machines, are tightly regulated. Here the authors reveal the molecular mechanism behind a unique form of GS regulation involving oligomer modulation.
- Maria A. Schumacher
- , Raul Salinas
- & Nicholas Lent
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Article
| Open AccessThe GET insertase exhibits conformational plasticity and induces membrane thinning
Tail-anchored (TA) membrane protein biogenesis is mediated by the GET insertase. Here, authors present cryo-EM and X-ray structures, MD simulations and functional data for human and fungal insertases showing membrane remodeling for TA insertion.
- Melanie A. McDowell
- , Michael Heimes
- & Irmgard Sinning
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Article
| Open AccessCryo-EM structures of the plant anion channel SLAC1 from Arabidopsis thaliana suggest a combined activation model
Phosphorylation-mediated activation of SLAC1 anion channel is crucial in plant responses for abiotic stresses including drought. Here, authors determine the open and closed structures of SLAC1, revealing how phosphorylation can activate SLAC1.
- Yeongmok Lee
- , Hyeon Seong Jeong
- & Sangho Lee
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Article
| Open AccessMechanistic insights into glycoside 3-oxidases involved in C-glycoside metabolism in soil microorganisms
Integrated experimental and computational approaches reveal functional and structural details of a key catabolic enzyme that oxidizes recalcitrant C-glycosides, abundant and biologically significant natural molecules, before deglycosylation.
- André Taborda
- , Tomás Frazão
- & Lígia O. Martins
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Article
| Open AccessIntra- and inter-molecular regulation by intrinsically-disordered regions governs PUF protein RNA binding
FBF-2 and LST-1 repress gld-1 mRNA expression to maintain C. elegans germline stem cells. The authors show that an intrinsically-disordered region of FBF-2 autoinhibits its RNA binding. LST-1 antagonizes this interaction to promote RNA binding.
- Chen Qiu
- , Zihan Zhang
- & Traci M. Tanaka Hall
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Article
| Open AccessA 5+1 assemble-to-activate mechanism of the Lon proteolytic machine
Many AAA+ (ATPases associated with diverse cellular activities) proteins function as a hexamer to remodel protein substrates. Here, the authors report the discovery of a pentameric form of the Lon AAA+ protease and show that it plays a role in the substrate-dependent activation of the AAA+ protein.
- Shanshan Li
- , Kan-Yen Hsieh
- & Chung-I Chang
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Article
| Open AccessFunctional and structural diversity in deubiquitinases of the Chlamydia-like bacterium Simkania negevensis
Intracellular bacteria use deubiquitinase effectors to avoid being targeted for autophagic clearance. The authors show that the Chlamydia-like bacterium Simkania negevensis encodes an unusually broad range of these enzymes, including members that specifically target linear and K6-linked ubiquitin chains.
- Vanessa Boll
- , Thomas Hermanns
- & Kay Hofmann
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Article
| Open AccessThe E3 ligase Riplet promotes RIG-I signaling independent of RIG-I oligomerization
Riplet conjugates K63-Ub chain to RIG-I in order to induce a robust antiviral response, but the mechanism of action remains unclear. Here, the authors show that Riplet recognizes RIG-I regardless of its RNA-bound status and promotes RIG-I signaling independent of RIG-I oligomerization.
- Wenshuai Wang
- , Benjamin Götte
- & Anna Marie Pyle
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Article
| Open AccessA closed translocation channel in the substrate-free AAA+ ClpXP protease diminishes rogue degradation
The translocation channel of ClpXP, which must open for degradation, is closed by an axial pore-2 loop when recognizing the ssrA degron. Here the authors show that the channel is also closed in the absence of substrate in cryo-EM structures and find that mutational destabilization of the closed-channel conformation changes substrate specificity.
- Alireza Ghanbarpour
- , Steven E. Cohen
- & Robert T. Sauer
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Article
| Open AccessStructural basis of bile salt extrusion and small-molecule inhibition in human BSEP
BSEP (ABCB11) is expressed in hepatocytes and extrudes bile salts into the canaliculi of the liver. Here, authors report cryo-EM structures of BSEP providing structural and functional insight into the mechanism of bile salt extrusion and small-molecule inhibition.
- Hongtao Liu
- , Rossitza N. Irobalieva
- & Kaspar P. Locher
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Article
| Open AccessCryo-EM structure of TMEM63C suggests it functions as a monomer
TMEM63s are mechanosensitive ion channels activated by hypo-osmolality. Here, the authors determine the cryo-EM structure of mouse TMEM63C confirming its predominant monomeric state and the significance of TM0-TM6 coupling in channel activity.
- Yuqi Qin
- , Daqi Yu
- & Shangyu Dang
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Article
| Open AccessCryo-electron tomography of NLRP3-activated ASC complexes reveals organelle co-localization
The authors characterized puncta in the ASC complex by correlative light microscopy and cryo-ET in cells and propose an ultrastructure of the ASC filament network.
- Yangci Liu
- , Haoming Zhai
- & Yorgo Modis
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Article
| Open AccesstrRosettaRNA: automated prediction of RNA 3D structure with transformer network
Here, authors develop trRosettaRNA, a deep learning-based approach for predicting RNA 3D structures. Blind tests demonstrate that the automated predictions compete effectively with top human predictions on natural RNAs.
- Wenkai Wang
- , Chenjie Feng
- & Jianyi Yang
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Article
| Open AccessStructures of the DarR transcription regulator reveal unique modes of second messenger and DNA binding
The molecular basis for 2nd messenger binding to the TetR family regulator (TFR), DarR, is unknown. Here the authors obtain DarR structures bound to adenine 2nd messengers and DNA, revealing both a new TFR allosteric binding site and DNA binding mode.
- Maria A. Schumacher
- , Nicholas Lent
- & Raul Salinas
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Article
| Open AccessMechanism of selective recognition of Lys48-linked polyubiquitin by macrocyclic peptide inhibitors of proteasomal degradation
Macrocyclic peptides were recently discovered as potent modulators of ubiquitin-mediated cellular signaling pathways. Here the authors used multidisciplinary approach to uncover how macrocyclic peptides that inhibit proteasomal degradation selectively recognize long Lys48-linked polyubiquitin chains.
- Betsegaw Lemma
- , Di Zhang
- & David Fushman
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Article
| Open AccessAsymmetric conformations and lipid interactions shape the ATP-coupled cycle of a heterodimeric ABC transporter
Multidrug resistance through active extrusion of molecules by transporters is a pressing clinical problem. Here, authors dissect the mechanism by which an ABC transporter from B. Subtilis binds and removes drugs by consuming the energy of ATP hydrolysis.
- Qingyu Tang
- , Matt Sinclair
- & Hassane S. Mchaourab
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Article
| Open AccessCryo-EM structures of human magnesium channel MRS2 reveal gating and regulatory mechanisms
Magnesium homeostasis is key for cellular functions. Here, authors report structures of human mitochondrial Mg2+ channel MRS2 and identified key residues in gating. This work provides insights into the gating and regulatory mechanisms of MRS2.
- Louis Tung Faat Lai
- , Jayashree Balaraman
- & Doreen Matthies
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Article
| Open AccessInadequate structural constraint on Fab approach rather than paratope elicitation limits HIV-1 MPER vaccine utility
It is still unclear why HIV-1 vaccines targeting MPER induce antibodies that fail to bind HIV. Here, the authors show that antibodies targeting membrane-proximal linear epitopes of virion spike proteins must generate relevant antibody paratopes and approach angles to ligate their quarry in a topologically restricted site.
- Kemin Tan
- , Junjian Chen
- & Mikyung Kim
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Article
| Open AccessStructural insights into the modulation of coronavirus spike tilting and infectivity by hinge glycans
In this work, the authors combine cryo-electron tomography of vitrified virions, mass spectrometry, modeling, molecular dynamics and infectivity assay and report that a hinge glycan on viral spike protein influences virus infection and immune evasion.
- David Chmielewski
- , Eric A. Wilson
- & Wah Chiu
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Article
| Open AccessStructural basis of peptide secretion for Quorum sensing by ComA
Quorum sensing is a regulatory mechanism controlling bacterial signaling and ComA, a conserved efflux pump, is responsible for the maturation and secretion of peptide signals. Here, authors determine the 3D structure and demonstrate its function as an ABC transporter.
- Lin Yu
- , Xin Xu
- & Min Luo
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Article
| Open AccessRNA recognition by Npl3p reveals U2 snRNA-binding compatible with a chaperone role during splicing
Here the authors identify the sequence bound by Npl3 and solve the structure of the complex using NMR. Npl3 binds directly to the U2 snRNA and melt the stem-loop I, suggesting a chaperoning role during spliceosome active site formation.
- Ahmed Moursy
- , Antoine Cléry
- & Frédéric H.-T. Allain
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Article
| Open AccessStructure of a heteropolymeric type 4 pilus from a monoderm bacterium
Here, Anger et al. report the structure of the type 4 pilus (T4P) from Streptococcus sanguinis. They show that the T4P architecture seen in diderm bacteria – where the N-terminal α-helices of pilin subunits are partially unfolded upon polymerisation – is conserved in distant monoderm species.
- Robin Anger
- , Laetitia Pieulle
- & Rémi Fronzes
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Article
| Open AccessDual function of OmpM as outer membrane tether and nutrient uptake channel in diderm Firmicutes
Outer membrane tethering is important for cell envelope integrity in diderm bacteria. Here, the authors present structures and functional analyses of the stalked porin OmpM, which is the main outer membrane tethering system within the Terrabacteria.
- Augustinas Silale
- , Yiling Zhu
- & Bert van den Berg
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Article
| Open AccessEnzymatic β-elimination in natural product O- and C-glycoside deglycosylation
Biological degradation of glycosides involves, alongside hydrolysis, β-elimination for glycosidic bond cleavage. Here, the authors report an O-glycoside β-eliminase from Agrobacterium tumefaciens that converts the C3-oxidized O-β-d-glucoside of phloretin into the aglycone and the 2-hydroxy-3-keto-d-glycal elimination product, and suggest convergent evolution of β-eliminase active sites for the cleavage of natural product 3-keto-O-glycosides.
- Johannes Bitter
- , Martin Pfeiffer
- & Bernd Nidetzky