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Article
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Insights into the inhibition of protospacer integration via direct interaction between Cas2 and AcrVA5
Here, the authors characterize an anti-CRISPR protein that prevents protospacer integration by Cas1-Cas2, providing structural insights that may benefit CRISPR-Cas systems research.
- Mingfang Bi
- , Wenjing Su
- & Xiaobing Mo
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Article
| Open Access
Emerging variants develop total escape from potent monoclonal antibodies induced by BA.4/5 infection
Many emerging SARS-CoV-2 variants partially escape the humoral immune response. Here, Liu et al. characterize 28 antibodies from BA.4/5 breakthrough infections and find attrition of neutralization and complete loss of function for variants with Spike mutations at positions 455 and 456.
- Chang Liu
- , Raksha Das
- & Gavin R. Screaton
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Functional protein dynamics in a crystal
Work by Klyshko and Kim et al. lays the foundation for simulating pump-probe experiments and demonstrates how the dynamic behaviour of proteins extends to the crystal environment, emphasizing the need for an ensemble view in understanding functional motions.
- Eugene Klyshko
- , Justin Sung-Ho Kim
- & Sarah Rauscher
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A hemoprotein with a zinc-mirror heme site ties heme availability to carbon metabolism in cyanobacteria
Heme is an abundant cofactor required by nearly all known organisms. Here, authors discover a cyanobacterial protein with a distinct Zn-mirror heme site, which may function to sense heme and regulate energy metabolism.
- Nicolas Grosjean
- , Estella F. Yee
- & Crysten E. Blaby-Haas
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A subgroup of light-driven sodium pumps with an additional Schiff base counterion
Light-driven sodium-pumping rhodopsins are unique ion transporters. Here, authors present a characterization of such rhodopsins with a modified active center allowing for efficient sodium transport under various environmental conditions.
- E. Podoliak
- , G. H. U. Lamm
- & K. Kovalev
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Structure-guided functional suppression of AML-associated DNMT3A hotspot mutations
DNMT3A R882H and R882C are mutation hotspots in acute myeloid leukemia. This study describes the structural and functional consequences of the DNMT3A R882H/R882C mutations which can provide a strategy for therapy of the disease mutations.
- Jiuwei Lu
- , Yiran Guo
- & Jikui Song
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Identifying a key spot for electron mediator-interaction to tailor CO dehydrogenase’s affinity
Carbon monoxide dehydrogenases (CODH) employ artificial electron mediators like viologens for biocatalysis, but little is known about the interaction between the mediators and the enzyme. Here, the authors discover the critical site for viologen interactions at the D-cluster of Carboxydothermus hydrogenoformans CODH2 via alanine mutations and crystallography, and report variants with increased ethyl viologen affinity.
- Suk Min Kim
- , Sung Heuck Kang
- & Yong Hwan Kim
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Structure and function of Semaphorin-5A glycosaminoglycan interactions
Semaphorin 5A (Sema5A) forms complexes with heparan and chondroitin sulfate proteoglycans to regulate neuronal migration. Here, the authors show that the thrombospondin-like repeat 4 (TSR4) of Sema5A enables glycosaminoglycan association, multimerization, and neural progenitor cell distribution.
- Gergely N. Nagy
- , Xiao-Feng Zhao
- & E. Yvonne Jones
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Methyl transfer in psilocybin biosynthesis
The natural hallucinogen psilocybin — produced by so-called magic mushrooms — holds promise for the treatment of depression and other mental health conditions. Here, the authors provide a structural and biochemical analysis of the Psilocybe methyl transferase PsiM that provides mechanistic insight into the last step of psilocybin biosynthesis.
- Jesse Hudspeth
- , Kai Rogge
- & Sebastiaan Werten
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A structure-based designed small molecule depletes hRpn13Pru and a select group of KEN box proteins
Here, the authors identify a small molecule degrader (XL44) for hRpn13 and solve the XL44-hRpn13 structure. XL44 induces apoptosis in myeloma cells with hRpn13 dependency and also targets KEN box proteins PCLAF and RRM2. Loss of hRpn13 and PCLAF abrogates XL44 restriction of cell viability.
- Xiuxiu Lu
- , Monika Chandravanshi
- & Kylie J. Walters
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The evolutionary origin of naturally occurring intermolecular Diels-Alderases from Morus alba
Diels-Alderases (DAs), enzymes catalyzing [4 + 2] cycloaddition reactions, are of high interest, but insights into their evolution are lacking. Here, the authors investigate the evolutionary origins of the intermolecular DAs in the biosynthesis of Moraceae plant-derived Diels-Alder-type secondary metabolites, suggesting they evolved from an ancestor functioning as a flavin adenine dinucleotide-dependent oxidocyclase.
- Qi Ding
- , Nianxin Guo
- & Xiaoguang Lei
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Legionella metaeffector MavL reverses ubiquitin ADP-ribosylation via a conserved arginine-specific macrodomain
The pathogen Legionella pneumophila mediates NAD+-dependent ubiquitination pathways upon infection. Here, the authors show the Legionella effector MavL reverses ubiquitin ADP-ribosylation to regulate these pathways. MavL represents a new macrodomain class specific for reversal of arginine ADP-ribosylation with distinct ADP-ribose binding features.
- Zhengrui Zhang
- , Jiaqi Fu
- & Chittaranjan Das
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Two DOT1 enzymes cooperatively mediate efficient ubiquitin-independent histone H3 lysine 76 tri-methylation in kinetoplastids
Trypanosoma brucei DOT1A and DOT1B methylate H3K76 without H2B-ubiquitin. Based on structural and enzymatic data, Frisbie et al. reveal a mechanism of how these enzymes cooperatively and efficiently tri-methylate H3K76 in a ubiquitin-independent way.
- Victoria S. Frisbie
- , Hideharu Hashimoto
- & Erik W. Debler
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Structure of orthoreovirus RNA chaperone σNS, a component of viral replication factories
Orthoreovirus σNS, essential for forming viral replication factories, has RNA chaperone activity that requires the association of σNS dimers into filamentous structures stabilized by domain-swapping interactions of the flexible N-terminal arms.
- Boyang Zhao
- , Liya Hu
- & B. V. Venkataram Prasad
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Structural and mechanistic insights into activation of the human RNA ligase RTCB by Archease
RTCB-type RNA ligases play important roles in tRNA splicing, the unfolded protein response and RNA repair. Here, Gerber et al. present structural snapshots of RTCB’s reaction cycle, and show how an activation complex with Archease primes RTCB for ligation.
- Janina Lara Gerber
- , Suria Itzel Morales Guzmán
- & Jirka Peschek
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A three-level regulatory mechanism of the aldo-keto reductase subfamily AKR12D
Here, the authors characterise an aldo-keto reductase AKRtyl, which belongs to a previously unidentified subfamily AKR12D. They uncover a complex mechanism of allosteric regulation that is mediated by 3 distinct states.
- Zhihong Xiao
- , Jinyin Zha
- & Shaobo Dai
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Dimerization-dependent serine protease activity of FAM111A prevents replication fork stalling at topoisomerase 1 cleavage complexes
FAM111A is a serine protease important for DNA replication and antiviral defense. Here, the authors report that the FAM111A dimerization is crucial for its proteolytic activity and for promoting DNA replication at trapped topoisomerase I.
- Sowmiya Palani
- , Yuka Machida
- & Yuichi J. Machida
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Chloride intracellular channel (CLIC) proteins function as fusogens
The Chloride Intracellular Channel (CLIC) protein family is highly conserved, yet their function remains a matter of ongoing research. Here, authors reveal their ability to facilitate membrane fusion, shedding light on their physiological role.
- Bar Manori
- , Alisa Vaknin
- & Yoni Haitin
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A streamlined approach to structure elucidation using in cellulo crystallized recombinant proteins, InCellCryst
SX experiments require thousands of high-quality microcrystals. Here, authors present a pipeline for protein crystallization in insect cells, including compartment screening and identification of physiological ligands from data collection in cellulo.
- Robert Schönherr
- , Juliane Boger
- & Lars Redecke
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Bacteria employ lysine acetylation of transcriptional regulators to adapt gene expression to cellular metabolism
The mechanisms underlying adaptation of bacteria to changing environmental conditions remain poorly understood. Here, the authors show bacteria using lysine acetylation of transcriptional regulators to adjust gene expression to changing conditions.
- Magdalena Kremer
- , Sabrina Schulze
- & Michael Lammers
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Substrate binding and catalytic mechanism of the Se-glycosyltransferase SenB in the biosynthesis of selenoneine
SenB is a Se-glycosyltransferase in the microbial biosynthesis pathway of selenoneine. Here, the authors perform the structure-function investigation, providing mechanistic insights into a two-step catalytic reaction of SenB.
- Wei Huang
- , Jun Song
- & Feng Long
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Article
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Substrate promiscuity of inositol 1,4,5-trisphosphate kinase driven by structurally-modified ligands and active site plasticity
InsP3 3-kinase phosphorylates 1,4,5-trisphosphate (InsP3) specifically at its secondary 3-hydroxyl group to generate a tetrakisphosphate. Here, the authors used a combination of methods to survey InsP3 3-kinase ligand specificity and determined that IP3K specificity surpasses that of its natural substrate, allowing it to bind diverse ligands with a primary hydroxyl in the reactive position and based on a carbohydrate moiety.
- María Ángeles Márquez-Moñino
- , Raquel Ortega-García
- & Beatriz González
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Cyclic peptides discriminate BCL-2 and its clinical mutants from BCL-XL by engaging a single-residue discrepancy
Pro-survival B-cell lymphoma-2 (BCL-2) family proteins BCL-2 and BCL-XL are the targets of anti-tumour drugs, but resistance is emerging. The authors present cyclic peptides against BCL-2 and BCL-XL, with a distinct mechanism of targeting characterised.
- Fengwei Li
- , Junjie Liu
- & Dalei Wu
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| Open Access
Poly-γ-glutamylation of biomolecules
Poly-γ-glutamate tails are a distinctive feature of folate and F420 cofactors, but it was unclear how these tails elongate while maintaining substrate specificity. Here, the authors discover that folylpolyglutamate synthase and γ-glutamyl ligase enzymes add successive L-glutamates to the termini of the growing γ-glutamyl chain in a processive mechanism.
- Ghader Bashiri
- , Esther M. M. Bulloch
- & Christopher J. Squire
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Molecular basis of SAP05-mediated ubiquitin-independent proteasomal degradation of transcription factors
SAP05, a secreted effector of the obligate parasitic bacteria phytoplasma, bridges host SPL and GATA transcription factors (TFs) to the 26 S proteasome subunit RPN10 for ubiquitination-independent degradation. Here, the authors report the details on how SAP05 interacts with SPL5, GATA18 and RPN10.
- Xiaojie Yan
- , Xinxin Yuan
- & Cheng Dong
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The synthetic NLR RGA5HMA5 requires multiple interfaces within and outside the integrated domain for effector recognition
An engineered sensor NLR RGA5HMA5 carrying multiple resurfaced interfaces was generated to confer complete resistance to the rice blast fungus strains expressing the non-corresponding effector AVR-PikD, paving a way to broaden the resistance spectra of NLRs.
- Xin Zhang
- , Yang Liu
- & You-Liang Peng
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Structural differences between the closely related RNA helicases, UAP56 and URH49, fashion distinct functional apo-complexes
UAP56 is an important factor in the TREX complex, which is responsible for mRNA export. Here the authors show that the closely related RNA helicases, UAP56 and URH49, exhibit different three-dimensional structures due to one amino acid change. Accordingly, they form distinct apo-complexes and function in the nuclear export of specific target mRNAs.
- Ken-ichi Fujita
- , Misa Ito
- & Seiji Masuda
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Disordered-to-ordered transitions in assembly factors allow the complex II catalytic subunit to switch binding partners
Here, the authors investigate the maturation of human respiratory Complex II, uncovering two metastable intermediates of maturation which suggest changes in intrinsic disorder ensure that the assembly steps occur in the correct sequence.
- Pankaj Sharma
- , Elena Maklashina
- & T. M. Iverson
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Multiple redox switches of the SARS-CoV-2 main protease in vitro provide opportunities for drug design
Here the authors demonstrate that the SARS-CoV-2 main protease (Mpro) is subject to redox regulation in vitro, reversibly switching between the enzymatically active dimer and the functionally dormant monomer through redox modifications of cysteine residues.
- Lisa-Marie Funk
- , Gereon Poschmann
- & Kai Tittmann
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Conformational coupling of the sialic acid TRAP transporter HiSiaQM with its substrate binding protein HiSiaP
Tripartite ATP-independent periplasmic (TRAP) transporters use an extra substrate binding protein to transport a variety of substrates in bacteria and archaea. Here the authors use a disulfide engineering approach to lock the TRAP transporter HiSiaPQM from H. influenzae in different conformational states for characterisation.
- Martin F. Peter
- , Jan A. Ruland
- & Gregor Hagelueken
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Tail-tape-fused virion and non-virion RNA polymerases of a thermophilic virus with an extremely long tail
The authors describe the structure and function of two evolutionarily diverged RNA polymerases of a thermophilic phage. One of the polymerases is fused to the phage tape measure protein, a virion component dictating the length of the phage tail.
- Anastasiia Chaban
- , Leonid Minakhin
- & Maria L. Sokolova
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Diverse array of neutralizing antibodies elicited upon Spike Ferritin Nanoparticle vaccination in rhesus macaques
An adjuvanted SARS-CoV-2 spike-ferritin nanoparticle vaccine can elicit antibodies with relatively broad sarbecovirus activity in non-human primates. Here, the authors isolate and structurally characterize several monoclonal antibodies providing insights into the targeted epitopes and broad reactivity.
- Rajeshwer S. Sankhala
- , Kerri G. Lal
- & M. Gordon Joyce
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Avapritinib-based SAR studies unveil a binding pocket in KIT and PDGFRA
Avapritinib, a potent inhibitor, offers hope for D842V-mutant GIST patients with high response rates; however, resistance and side effects remain challenges. Here, crystal structures shed light on this and reveal a Gα-pocket for drug development.
- A. Teuber
- , T. Schulz
- & D. Rauh
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Structural insights into the regulation, ligand recognition, and oligomerization of bacterial STING
Here the authors present the crystal structure of a bacterial STING. The structure shows that bacterial STING can modulate immune responses by forming anti-parallel dimers or, in certain species, through the presence of a long lid.
- Mei-Hui Hou
- , Yu-Chuan Wang
- & Yeh Chen
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The Mycobacterium tuberculosis methyltransferase Rv2067c manipulates host epigenetic programming to promote its own survival
Singh et al. show how the M. tuberculosis methyltransferase Rv2067c outsmarts host epigenetic machinery by methylating histone H3 prior to its assembly into nucleosomes, thereby ensuring the pathogen’s intracellular survival/success.
- Prakruti R. Singh
- , Venkatareddy Dadireddy
- & Valakunja Nagaraja
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Autoregulation of the LIM kinases by their PDZ domain
LIM domain kinases are key regulators of cofilin and consequently actin severing. Here, the authors show that the LIMK PDZ domain is important for autoregulation using a conserved surface distal to the canonical PDZ-binding cleft.
- Gabriela Casanova-Sepúlveda
- , Joel A. Sexton
- & Titus J. Boggon
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A DARPin promotes faster onset of botulinum neurotoxin A1 action
Botulinum neurotoxins (BoNTs), the causative agents of the disease botulism, are potent biological toxins. Here the authors use Designed Ankyrin Repeat Proteins (DARPins) to probe BoNT structure and function: DARPin-F5 that completely blocks SNAP25 substrate cleavage by BoNT/A1 in vitro was identified.
- Oneda Leka
- , Yufan Wu
- & Richard A. Kammerer
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| Open Access
A single C-terminal residue controls SARS-CoV-2 spike trafficking and incorporation into VLPs
Dey et al. use structure-function methods to show that partial mimicry of the coatomer-binding motif in the SARS-CoV-2 spike is crucial for its release post coatomer-dependent delivery, thus ensuring optimal spike fusogenicity and VLP incorporation.
- Debajit Dey
- , Enya Qing
- & S. Saif Hasan
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| Open Access
ZNF524 directly interacts with telomeric DNA and supports telomere integrity
ZNF524 is a newly described protein that binds to telomeres, the ends of linear chromosomes. ZNF524 promotes the presence of two members of the shelterin complex, TRF2/RAP1, at telomeres, and prevents genomic instability.
- Hanna Braun
- , Ziyan Xu
- & Dennis Kappei
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Article
| Open Access
Structural and thermodynamic insights into antibody light chain tetramer formation through 3D domain swapping
Atomic-level structural examinations of antibody light chain aggregates are sparse. Here, the authors find an antibody light chain that maintains an equilibrium between monomeric and tetrameric states and show with its 3D structure that it engages in 3D domain swapping within its variable region.
- Takahiro Sakai
- , Tsuyoshi Mashima
- & Shun Hirota
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| Open Access
A multi-reservoir extruder for time-resolved serial protein crystallography and compound screening at X-ray free-electron lasers
Protein serial crystallography at X-ray free-electron lasers (XFELs) is a powerful technique for structure determination. Here, authors present a device for sample delivery designed to abate challenges to non-specialists allowing for compound screening.
- Maximilian Wranik
- , Michal W. Kepa
- & Jörg Standfuss
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| Open Access
Structural basis of a redox-dependent conformational switch that regulates the stress kinase p38α
p38α is a kinase that regulates many cellular processes. Here authors report that redox fluctuations induce conformational changes to fine-tune the p38α activity beyond its activation loop phosphorylation.
- Joan Pous
- , Blazej Baginski
- & Maria J. Macias
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Pyroptosis inhibiting nanobodies block Gasdermin D pore formation
Pyroptosis has been implicated in many diseases with aberrant inflammation. Here, Kopp et al. characterize single-chain nanobodies targeting the human gasdermin D protein as tools to inhibit pyroptosis.
- Anja Kopp
- , Gregor Hagelueken
- & Matthias Geyer
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Illuminating 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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| Open Access
Discovery 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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| Open Access
Stochastic 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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Structure-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 Access
Structures 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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| Open Access
The 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
Modulation of peroxisomal import by the PEX13 SH3 domain and a proximal FxxxF binding motif