Translation dynamics in human cells visualized at high resolution reveal cancer drug action

Science, Год журнала: 2023, Номер 381(6653), С. 70 - 75

Опубликована: Июль 6, 2023

Ribosomes catalyze protein synthesis by cycling through various functional states. These states have been extensively characterized in vitro, but their distribution actively translating human cells remains elusive. We used a cryo-electron tomography-based approach and resolved ribosome structures inside with high resolution. revealed the of elongation cycle, Z transfer RNA binding site, dynamics expansion segments. Ribosome from treated Homoharringtonine, drug against chronic myeloid leukemia, how translation were altered situ resolve small molecules within active site ribosome. Thus, structural effects can be assessed at resolution cells.

Язык: Английский

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Nuclear transport proteins: structure, function, and disease relevance

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Ноя. 10, 2023

Abstract Proper subcellular localization is crucial for the functioning of biomacromolecules, including proteins and RNAs. Nuclear transport a fundamental cellular process that regulates many macromolecules within nuclear or cytoplasmic compartments. In humans, approximately 60 are involved in transport, nucleoporins form membrane-embedded pore complexes, karyopherins cargoes through these Ran system ensure directed rapid transport. Many play additional essential roles mitosis, biomolecular condensation, gene transcription. Dysregulation linked to major human diseases such as cancer, neurodegenerative diseases, viral infections. Selinexor (KPT-330), an inhibitor targeting export factor XPO1 (also known CRM1), was approved 2019 treat two types blood cancers, dozens clinical trials ongoing. This review summarizes three decades research data this field but focuses on structure function individual from recent studies, providing cutting-edge holistic view role health disease. In-depth knowledge rapidly evolving has potential bring new insights into biology, pathogenic mechanisms, therapeutic approaches.

Язык: Английский

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AlphaFold2 protein structure prediction: Implications for drug discovery

Current Opinion in Structural Biology, Год журнала: 2023, Номер 78, С. 102526 - 102526

Опубликована: Янв. 6, 2023

Язык: Английский

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Cryo-electron tomography on focused ion beam lamellae transforms structural cell biology

Nature Methods, Год журнала: 2023, Номер 20(4), С. 499 - 511

Опубликована: Март 13, 2023

Язык: Английский

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Bridging structural and cell biology with cryo-electron microscopy

Nature, Год журнала: 2024, Номер 628(8006), С. 47 - 56

Опубликована: Апрель 3, 2024

Язык: Английский

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AlphaFold2 structures guide prospective ligand discovery

Science, Год журнала: 2024, Номер 384(6702)

Опубликована: Май 16, 2024

AlphaFold2 (AF2) models have had wide impact but mixed success in retrospective ligand recognition. We prospectively docked large libraries against unrefined AF2 of the σ

Язык: Английский

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TomoTwin: generalized 3D localization of macromolecules in cryo-electron tomograms with structural data mining

Nature Methods, Год журнала: 2023, Номер 20(6), С. 871 - 880

Опубликована: Май 15, 2023

Cryogenic-electron tomography enables the visualization of cellular environments in extreme detail, however, tools to analyze full amount information contained within these densely packed volumes are still needed. Detailed analysis macromolecules through subtomogram averaging requires particles first be localized tomogram volume, a task complicated by several factors including low signal noise ratio and crowding space. Available methods for this suffer either from being error prone or requiring manual annotation training data. To assist crucial particle picking step, we present TomoTwin: an open source general model cryogenic-electron tomograms based on deep metric learning. By embedding information-rich, high-dimensional space that separates according their three-dimensional structure, TomoTwin allows users identify proteins de novo without manually creating data retraining network locate new proteins.

Язык: Английский

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HIV-1 capsids enter the FG phase of nuclear pores like a transport receptor

Nature, Год журнала: 2024, Номер 626(8000), С. 843 - 851

Опубликована: Янв. 24, 2024

Abstract HIV-1 infection requires nuclear entry of the viral genome. Previous evidence suggests that this proceeds through pore complexes (NPCs), with 120 × 60 nm capsid squeezing an approximately 60-nm-wide central channel 1 and crossing permeability barrier NPC. This can be described as FG phase 2 is assembled from cohesively interacting phenylalanine–glycine (FG) repeats 3 selectively permeable to cargo captured by transport receptors (NTRs). Here we show assemblies target NPCs efficiently in NTR-independent manner bind directly several types repeats, including barrier-forming cohesive repeats. Like NTRs, readily partitions into vitro serve NPC mimic excludes much smaller inert probes such mCherry. Indeed, protein greatly enhanced assembly, which also allows encapsulated clients enter. Thus, our data indicate behaves like NTR, its interior serving a container. Because capsid-coating trans -acting NTRs would increase diameter 10 or more, suggest ‘self-translocating’ undermines size restrictions imposed scaffold, thereby bypassing otherwise effective infection.

Язык: Английский

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A quantitative map of nuclear pore assembly reveals two distinct mechanisms

Nature, Год журнала: 2023, Номер 613(7944), С. 575 - 581

Опубликована: Янв. 4, 2023

Understanding how the nuclear pore complex (NPC) is assembled of fundamental importance to grasp mechanisms behind its essential function and understand role during evolution eukaryotes

Язык: Английский

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Pragmatic Coarse-Graining of Proteins: Models and Applications

Journal of Chemical Theory and Computation, Год журнала: 2023, Номер 19(20), С. 7112 - 7135

Опубликована: Окт. 3, 2023

The molecular details involved in the folding, dynamics, organization, and interaction of proteins with other molecules are often difficult to assess by experimental techniques. Consequently, computational models play an ever-increasing role field. However, biological processes involving large-scale protein assemblies or long time scale dynamics still computationally expensive study atomistic detail. For these applications, employing coarse-grained (CG) modeling approaches has become a key strategy. In this Review, we provide overview what call pragmatic CG models, which strategies combining, at least part, physics-based implementation top-down approach their parametrization. particular, focus on most residues represented two beads, allowing retain some degree chemical specificity. A description main modern is provided, including review recent applications outlook future perspectives

Язык: Английский

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