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Kozai, Fernandez-Martinez et al. use high-speed atomic force microscopy to study the permeability barrier of yeast nuclear pore complexes. They show that karyopherins remodel a central plug that shapes barrier dynamics and disorder within the pore.

Alveolar rhabdomyosarcoma is a clinically challenging disease due to the lack of druggable targets. Here the authors show preclinical evidence for ATR inhibitors as a therapeutic option for alveolar rhabdomyosarcoma.

Actin mediates insulin secretion in pancreatic β-cells through remodeling. Here, authors report the in situ structure of actin remodeling and quantify changes in architecture, alignment, and interactions during glucose-stimulated insulin secretion.

A virtual screen of the GPCR D3R based on a homology model prior to publication of the crystal structure and a subsequent virtual screen based on the crystal structure of the receptor once it became available both identified new ligands with verified activities.

A chemical genetic screen identified inhibitors of an essential transporter from Mycobacterium tuberculosis. Here authors determine atomic structures of EfpA that indicate that it is a lipid transporter, and multiple modes of inhibition that can act synergistically against tuberculosis.

A global map of human subcellular architecture yields protein complex structures, reveals protein functions, identifies assemblies with multiple localizations or cell-type specificity and decodes paediatric cancer genomes.

Affinity tagging, mass spectroscopy and a tailor-made scoring system are used to identify 497 high-confidence interactions between human proteins and human immunodeficiency virus proteins.

A human–SARS-CoV-2 protein interaction map highlights cellular processes that are hijacked by the virus and that can be targeted by existing drugs, including inhibitors of mRNA translation and predicted regulators of the sigma receptors.

MRP4 is an ATP-binding cassette transporter that transports prostanoids, a group of signaling molecules. The authors use cryo-EM to visualize the transport cycle and characterize its substrate selectivity.

The transcription cofactor CBF-β is shown to regulate the ability of HIV-1 to evade host restriction mediated by the deaminase APOBEC3; it acts by interacting with the HIV protein Vif, so disrupting the Vif–CBF-β interaction could provide a new therapeutic target against HIV-1 infection.

Orphan transporters can be found in over 20 families in the SLC superfamily. Here, the authors show that human SLC22A10 is a unitary pseudogene due to a fixed missense mutation, P220; while in great apes, its orthologs transport sex steroid conjugates.

Single-molecule calibrated live microscopy and computational modelling have revealed that human nuclear pore complex assembly takes different pathways during the exit from mitosis and during nuclear growth in interphase.

The proteasome complexes, composed of 20S core particles and one or two regulatory particles (proteasome activators), degrade most eukaryotic proteins. Here, the authors identify a sequence motif and resolve its interactions mediating the activation of the human 20S proteasome.

X-ray crystallography, cryo-electron microscopy, structural modelling, biochemistry, cell biology, and evolutionary analysis enable characterization of ORF2p, the reverse transcriptase of the ancient ‘parasitic’ LINE-1 retrotransposon that has written around one-third of the human genome.

Structural, biochemical, and modeling studies reveal how the non-canonical RNA Pol II subunit Gdown1 precludes general transcription factor interactions with Pol II(G) to repress transcriptional activity in the absence of Mediator.

Polyketide synthase 13 from mycobacteria was purified endogenously ‘in action’ with wild-type substrates bound. Structures by cryo-EM define multiple states of acyl carrier proteins in the final step of mycolic acid synthesis by a key drug target.

Network analyses of protein–protein, genetic and drug–gene interactions have typically been limited to analyses at the whole-protein and whole-gene levels. This Review discusses how high-resolution network analyses at the domain and residue levels are providing valuable insights into diverse research fields that range from structural biology to human disease.

The structure of the yeast nuclear pore complex, determined at sub-nanometre precision using an integrative approach that combines a wide range of data, reveals details of its architecture, transport mechanism and evolutionary origins.

Crystallography and mutagenesis analyses examine how HIV-1 Nef interacts with AP2 to enable CD4 binding and downregulation and reveal the role of a Nef pocket that is also involved in downregulation of class I MHC.

Organic cation transporters are important drug transporters that influence therapeutic outcomes. Here, the authors find that these transporters are regulated by tyrosine phosphorylation and propose that tyrosine kinase inhibitors can influence drug transporter function through post-translational mechanisms.

DNA origami has shown that principles of molecular recognition can be used to reshape biomolecules into nonphysiological forms. The design and synthesis of a continuous, 12-helix polypeptide that spontaneously self-assembles into a defined tetrahedron now demonstrates that protein structures can be similarly manipulated.

Group II chaperonins, such as TriC/CCT, have a build-in lid that can cover the folding chamber and functions in an analogous way to the GroES-like proteins used by their Group I counterparts. Structural and modeling data suggest an allosteric mechanism of TriC lid closure that differs from GroES–GroEL systems.

The scope of structural genomics has recently been estimated by simulation of several target selection strategies based on the currently known protein sequence families. Useful characterization of most protein sequences will be possible by protein structure modeling, if structures of ∼16,000 carefully selected protein domains are determined experimentally. In the absence of globally coordinated target selection, three times as many structures may be required.

Ingenious computational comparisons involving complete genomic sequences have predicted many new functional links between proteins, without relying on homologies to characterized proteins. These new methods complement the large-scale experimental determination of protein function, and will ultimately contribute to complete and powerful models of biological pathways and assemblies.

The γ-tubulin ring complex (γTuRC) nucleates microtubules in the cell. The functional, closed state of yeast γTuRC is now visualized, and its microtubule-nucleating activity is found to be species specific.

The combination of cell-free protein expression and combinatorial dual labeling–aided NMR analysis allows for the rapid backbone structure assessment of human membrane proteins.

Given the recent successes in determining membrane-protein structures, we explore the tractability of determining representatives for the entire human membrane proteome. This proteome contains 2,925 unique integral α-helical transmembrane-domain sequences that cluster into 1,201 families sharing more than 25% sequence identity. Structures of 100 optimally selected targets would increase the fraction of modelable human α-helical transmembrane domains from 26% to 58%, providing structure and function information not otherwise available.

The wealth of genomic data for pathogens that cause tropical diseases hold considerable promise for the discovery of novel drugs. An international consortium describes how the TDR Targets database integrates this data with related biochemical and pharmacological data to facilitate the identification and prioritization of drug targets.

The X-ray crystal structure of a member of the Ca²⁺/H⁺ (CAX) antiporter family from Saccharomyces cerevisiae in a cytosol-facing, substrate-bound conformation is solved; using the structure, a mechanism by which members of the Ca²⁺:cation (CaCA) superfamily facilitate Ca²⁺ transport across cellular membranes is proposed.

The X-ray crystal structure of a high-affinity phosphate importer in an inward-facing, occluded state in the presence of phosphate is reported; this is the first structure of a membrane protein involved in inorganic phosphate uptake and the first crystal structure of a eukaryotic MFS transporter.

The molecular architecture of protein complexes can be determined using an optimal approach for isolating GFP-tagged complexes at native levels, combined with cross-linking, mass spectrometry analysis, and structure modeling from mass spectrometry-derived distance restraints.

Large-scale genetic datasets and deep learning approaches are being used to model the structures of proteins or protein complexes. This Review describes approaches based on coevolution, deep mutational scanning and genome-scale genetic or chemical–genetic interaction mapping and their application and integration to inform structural modelling.