Structural biology

SARS-CoV-2 infection can cause coagulopathic events. Kuhn et al. show by cryo-ET how the Spike protein impacts platelet morphology by binding to the platelet surface, leading to micro-activation; and investigate integrin as possible point of contact.

Mitochondrial fatty acid synthesis (mtFAS) generates the precursor for lipoic acid synthesis, but the role of longer fatty acid products has remained unclear. Here, the authors generated an engineered variant of human 2E-enoyl-ACP reductase (MECR) of mtFAS to study the role of long chain fatty acids.

Glycerol flux across the plasma membrane is critical to metabolism and linked to disease. Here, authors present the cryo-EM structure of the glycerol channel AQP7 composed of two adhering tetramers and displaying well-defined densities in the central pore.

Plant biosynthetic enzymes rapidly evolve to catalyze specialized reactions. Here, the authors present the crystal structure and mechanism of COSY, the enzyme involved in coumarin biosynthesis of the BAHD-acyltransferase family that catalyzes an intramolecular acyl transfer reaction through a proton exchange mechanism.

SARS-CoV-2 variants of concern continue to emerge, reducing vaccine efficacy and limiting therapeutic options. Here, Chen and colleagues describe the identification and design of shark nanobodies with pansarbecovirus activity.

The authors report a systematic analyses of blood biomarkers for metabolism against the whole spectrum of diseases in 100,000 individuals and reveals a prominent role of numerous metabolic biomarkers as risk markers beyond heart disease and diabetes.

Viruses can cause Colony Collapse Disorder, leading to large losses of honeybee hives globally. In this study, the authors solve capsid structures of honeybee-infecting Lake Sinai viruses and identify distinct features, which advances understanding of viral dynamics, assembly and infection mechanisms.

The Ca_V2.3 channel is involved in synaptic plasticity and neurological disorders. Here, authors resolve the human Ca_V2.3 structure to explore functional heterogeneity of VSDs and elucidated the closed- and open-state inactivation mechanisms of the channel.

Follicle stimulating hormone (FSH) is a glycoprotein hormone the functions of which are mediated by a G protein-coupled receptor, FSHR. Here, Duan et al. report cryo-EM structures of FSHR in active and inactive states, suggesting the molecular basis of FSH and small allosteric agonist-mediated FSHR activation.

Relaxin family peptide receptor 4 (RXFP4) regulates pleiotropic biological processes. Here, authors report cryo-EM structures revealing the ligand-binding modes and key determinants of peptidomimetic agonism and subtype selectivity

Cagβ is an ATPase in the H. pylori CagType4 secretion system essential for delivering the CagA effector to host cells. Here, authors present crystal structures of hexameric apo-Cagβ and Cagβ trapped in the monomeric state by its regulator CagZ, uncovering the regulatory mechanisms of Cagβ.

Exocytosis is a fundamental cellular process. Here, the authors report an unusual exocytosis mechanism in the silicified cell wall of diatoms, in which membrane patches are discarded.

Biological processes can be regulated via oligomerization of macromolecules into high-order symmetric structures. Here, authors reported high-order structure of RNA polymerase and its role in regulation of gene expression in pathogenic bacterium.

Hepatitis B virus (HBV) capsid assembly modulators (CAM) represent a recent class of anti-HBV antivirals. Structural approaches provide limited conformational information on the CAM-induced off-path assemblies. Here, authors use solid-state NMR to establish a structural view on assembly modulation of the HBV capsid.

In this work, the authors show that metamorphism in the post-translationally modified TDP-43 prion-like domain encodes determinants that command mechanisms with major relevance in disease and stress the relevance of post-translationally modified chains as the targets for disease intervention.

Hepatitis C virus (HCV) uses a hybrid entry mechanism. Upon exposure to low pH, envelope glycoprotein E2 releases an internal loop into the host membrane. Here we show the amino terminal region is a critical determinant for membrane interaction, providing insights into the HCV entry mechanism.

In this work the authors investigate the structure-sequence dependance. The ability to design and characterize proteins at interfaces between three common folds suggests that fold switching is an intrinsic feature of protein folding language and likely important in the evolution of protein structure and function.

The molecular mechanisms underlying the formation of biomolecular condensates have not been fully elucidated. Here the authors show that the LLPS propensity, dynamics, and encapsulation efficiency of designed peptide condensates can be tuned by subtle changes to the peptide composition.

BRD4-NUT’s bipartite binding and activation of p300 in NUT carcinoma nucleates a feed-forward spread of histone hyperacetylation and chromatin condensation that sustains aberrant pro-proliferation gene transcription and perpetual tumor cell growth.

The ZIP family (SLC39A) is involved in transition metal homeostasis. Here, authors use integrated approaches to conclude that the ZIP from Bordetella bronchiseptica (BbZIP) utilizes the elevator-type transport mechanism to achieve alternating access.

Here, using cryo-electron microscopy and solution NMR, the authors reveal the structural and dynamic mechanisms underlying the signaling versatility of a muscarinic receptor regulated by orthosteric and allosteric ligands.

In this work the authors report the cryo-EM structure of the laminin polymer node and reveal the molecular basis of calcium-dependent formation of laminin lattice. The work provides insights into laminin polymerization defects manifesting in human disease.

The authors report the Cryo-EM of hnRNPDL-2 fibrils. The structure highlights features of a functional amyloid associated with limb-girdle muscular dystrophy-3 and explains how alternative splicing controls the assembly of this ribonucleoprotein.

T7 RNA polymerase (RNAP) is widely used for synthesizing RNA molecules with synthetic modifications and unnatural base pairs (UBPs). Here, authors show the structural basis of how UBPs are recognized as template and substrate, providing mechanistic insights into UBP transcription by T7 RNAP.

In this work, the authors report Cryo-EM structures of the signaling complexes of human GPR21, an orphan GPCR and a potential metabolic disease target, and reveal unique receptor activation conformation when bound to downstream signaling proteins in the absence of any ligand.

Here the authors establish the SPOC domain as a universal reader of the RNA Pol II CTD code and a versatile reader of phosphoserine marks found in co- and post-transcriptional regulators such as m6A writer and reader proteins.

RBR E3 ubiquitin ligases utilise a 2-step catalytic mechanism previously defined for only few of the RBR family members. Here, the authors examine the poorly studied RBRs HOIL-1 and RNF216 to define general principles of RBR catalysis and regulation and identify specific functional differences.

Conformational heterogeneity is key to understand how macromolecular function and structure converge. Here, the authors propose an algorithm designed to estimate structural landscapes directly from Cryo-EM particle images.

TLR3 activates a potent immune response by binding to dsRNA. Here the authors report cryo-EM analyses to show that TLR3 dimers laterally form a higher multimeric complex along dsRNA, providing the basis for cooperative binding and efficient signal transduction.

A subset of Sec14 domain proteins use their gated hydrophobic pocket to bind and transport lipids. Here the authors provide structural and biochemical data revealing how the Sec14-fold of a Rho-GEF forms a surface groove that interacts with lysolipids.

The nucleolus is a liquid-liquid phase separation droplet that dynamically changes under stress. Here, the authors report PQBP5/NOL10 is a critical component of the nucleolus, maintaining its structure and position in the nucleus during osmotic stress.

The multifunctional GSDMB protein is an important molecule in human immunity. Here, the authors decipher the molecular mechanisms of GSDMB targeting by the bacterial virulence factor IpaH7.8 and provide insights into GSDMB-mediated pyroptosis.

Neuromedin U receptor 2 is an emerging attractive target for treating obesity. Here, a Cryo-EM structure of NmU-25–NMU2–G_i1 provides the structural basis for the designation of highly selective drugs.

The authors identify nanobodies from immunized alpaca with broadly neutralizing activity against SARS-CoV-1, SARS-CoV-2 variants, and major sarbecoviruses. One representative nanobody binds to a highly conserved epitope on RBD and protects K18-hACE2 mice from Omicron and Delta infection.

Combining high-speed AFM, single molecule recognition force spectroscopy, and molecular dynamics simulations Zhu, Canena, Sikora et al. characterize the interaction dynamics of the trimeric spike protein of SARS-CoV-2 wt, and delta and omicron variants with its entry receptor ACE2. While delta variant increases avidity by multivalent binding to ACE2, omicron variant shows an extended binding lifetime.

SARM1 is a key player in axon degeneration. Here, the authors generate a nanobody, which specifically recognizes the NMN-bound state of SARM1 and helps resolve the SARM1 structure in an intermediate state of activation.

Specific ssDNA binding proteins promote the annealing of complementary strands. Here the authors reveal an intermediate of annealing in which a duplex DNA is bound in an unusual conformation that is highly extended and unwound for the ssDNA binding protein Redβ from bacteriophage λ.

Coxsackievirus A16 (CVA-16) causes hand, food and mouth disease in infants and young children, however, currently there are neither anti-virals nor vaccines available for treatment. Here, Zhang et al. characterize two CVA16-specific neutralizing monoclonal antibodies, 9B5 and 8C4. They provide evidence for their prophylactic and therapeutic application in vivo in mice and perform CryoEM to show that both antibodies target different epitopes on the viral capsid.

Micropatterning on electron microscopy grids enables control of cell positioning and arrangement. Here, the authors describe detailed nanoscale characterization of a micropatterning workflow for reproducible molecular characterization through cryo-ET

In this work, Blair and co-authors used cryo-EM and in vitro assays to show that human Ligase 1 (Lig1) and Flap Endonuclease 1 (FEN1) form a toolbelt with the sliding clamp PCNA coordinating the sealing of Okazaki fragments.

The streptococcal enzymes IdeS and EndoS cleave IgG antibodies with exquisite substrate specificity, which has enabled their development as clinical and biotechnological tools. Here, the authors present crystal structures of both enzymes in complex with their IgG1 Fc substrate.

Observation of the chemical and conformational dynamics of biomolecules by diffraction methods is impeded by several physical artifacts. The authors present an extensible framework for accurate correction of such data that can keep pace with rapid developments in diffraction methods.

Here the authors use structural analyses to show that an intrinsically disordered transcription activation domain in the oncogene BRD4-NUT binds to and activates p300. This in-turn drives formation of higher-order, acetylation-dependent chromatin condensates.

During photosynthesis, light energy is harvested by an antenna systems and delivered to the reaction centers (RCs) for charge separation and electron transfer (ET). The authors report cryo-EM structures of two forms of RC from the microaerophilic Chloracidobacterium thermophilum (CabRC), providing a structural basis for ET within the CabRC.

In this study, authors have solved cryo-EM structures of a bacteriophytochrome in its dark-adapted and illuminated states. The structures reveal the structural mechanism for photoactivation of the phytochrome.

Eps15-homology domain containing proteins comprise a family of dynamin-related ATPases. Here, Melo et al. use cryo-electron tomography to determine the membrane-bound EHD4 structure, therefore clarifying the membrane binding and oligomerization mode.

BAF and PBAF are SWI/SNF family chromatin remodeling complexes that create nucleosome-depleted regions for transcription activation. Here the authors report the structure of a 13-subunit human PBAF in complex with acetylated nucleosome in ADP-BeF₃-bound state that provides structural insights into PBAF-mediated nucleosome association.

The authors describe the VTD-deubiquitinases, a new eukaryotic enzyme family that is distantly related to herpesviral large tegument proteins. Structures of two family members with different linkage preferences allow insights into the mechanism and chain-specificity of this unusual deubiquitinase class.

N-degron pathways play an important role in maintaining protein homeostasis. Here, Li et al. demonstrates an additional non-Ac/N-degron pathway, in which N-terminal non-acetylated small residue degrons (Ser, Ala, or Cys) are recognized by CRL2^ZER1/ZYG11B and targeted for protein degradation.