Ranking Peptide Binders by Affinity with AlphaFold**

Angewandte Chemie International Edition, Год журнала: 2022, Номер 62(7)

Опубликована: Дек. 21, 2022

AlphaFold has revolutionized structural biology by predicting highly accurate structures of proteins and their complexes with peptides other proteins. However, for protein-peptide systems, we are also interested in identifying the highest affinity binder among a set candidate peptides. We present novel competitive binding assay using to predict receptor presence two For systems which individual well predicted, captures higher bound state, peptide unbound form statistical significance. test application on six protein receptors have experimental affinities several find that is best suited medium strong binders adopt stable secondary upon binding.

Язык: Английский

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Intranuclear Nanoribbons for Selective Killing of Osteosarcoma Cells

Angewandte Chemie International Edition, Год журнала: 2022, Номер 61(44)

Опубликована: Сен. 14, 2022

Herein, we show intranuclear nanoribbons formed upon dephosphorylation of leucine-rich L- or D-phosphopeptide catalyzed by alkaline phosphatase (ALP) to selectively kill osteosarcoma cells. Being dephosphorylated ALP, the peptides are first transformed into micelles and then converted nanoribbons. The peptides/assemblies aggregate on cell membranes, enter cells via endocytosis, finally accumulate in nuclei (mainly nucleoli). Proteomics analysis suggests that assemblies interact with histone proteins. rapidly nontoxic normal Moreover, repeated stimulation sensitizes cancer rather than inducing resistance. This work not only illustrates a novel mechanism for nucleus targeting, but may also pave new way killing minimizing drug

Язык: Английский

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Applications and prospects of cryo-EM in drug discovery

Military Medical Research, Год журнала: 2023, Номер 10(1)

Опубликована: Март 6, 2023

Abstract Drug discovery is a crucial part of human healthcare and has dramatically benefited lifespan life quality in recent centuries, however, it usually time- effort-consuming. Structural biology been demonstrated as powerful tool to accelerate drug development. Among different techniques, cryo-electron microscopy (cryo-EM) emerging the mainstream structure determination biomacromolecules past decade received increasing attention from pharmaceutical industry. Although cryo-EM still limitations resolution, speed throughput, growing number innovative drugs are being developed with help cryo-EM. Here, we aim provide an overview how techniques applied facilitate discovery. The development typical workflow technique will be briefly introduced, followed by its specific applications structure-based design, fragment-based discovery, proteolysis targeting chimeras, antibody repurposing. Besides cryo-EM, innovation involves other state-of-the-art such artificial intelligence (AI), which increasingly active diverse areas. combination AI provides opportunity minimize automation, throughput interpretation medium-resolution maps, tends new direction future rapid make indispensable modern

Язык: Английский

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Protein Structure Prediction: Challenges, Advances, and the Shift of Research Paradigms

Genomics Proteomics & Bioinformatics, Год журнала: 2023, Номер 21(5), С. 913 - 925

Опубликована: Март 30, 2023

Abstract Protein structure prediction is an interdisciplinary research topic that has attracted researchers from multiple fields, including biochemistry, medicine, physics, mathematics, and computer science. These adopt various paradigms to attack the same problem: biochemists physicists attempt reveal principles governing protein folding; mathematicians, especially statisticians, usually start assuming a probability distribution of structures given target sequence then find most likely structure, while scientists formulate as optimization problem — finding structural conformation with lowest energy or minimizing difference between predicted native structure. fall into two statistical modeling cultures proposed by Leo Breiman, namely, data algorithmic modeling. Recently, we have also witnessed great success deep learning in prediction. In this review, present survey efforts for We compare adopted different emphasis on shift era learning. short, techniques, neural networks, considerably improved accuracy prediction; however, theories interpreting networks knowledge folding are still highly desired.

Язык: Английский

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De novo protein identification in mammalian sperm using in situ cryoelectron tomography and AlphaFold2 docking

Cell, Год журнала: 2023, Номер 186(23), С. 5041 - 5053.e19

Опубликована: Окт. 20, 2023

To understand the molecular mechanisms of cellular pathways, contemporary workflows typically require multiple techniques to identify proteins, track their localization, and determine structures in vitro. Here, we combined cryoelectron tomography (cryo-ET) AlphaFold2 modeling address these questions how mammalian sperm are built situ. Our cryo-ET subtomogram averaging provided 6.0-Å reconstructions axonemal microtubule structures. The well-resolved tertiary allowed us unbiasedly match sperm-specific densities with 21,615 AlphaFold2-predicted protein models mouse proteome. We identified Tektin 5, CCDC105, SPACA9 as novel microtubule-associated proteins. These proteins form an extensive interaction network crosslinking lumen doublet microtubules, suggesting roles modulating mechanical properties filaments. Indeed, Tekt5 −/− possess more deformed flagella 180° bends. Together, our studies presented a visual proteomics workflow shed light on vivo functions 5.

Язык: Английский

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Mechanomemory in protein diffusivity of chromatin and nucleoplasm after force cessation

Proceedings of the National Academy of Sciences, Год журнала: 2023, Номер 120(13)

Опубликована: Март 21, 2023

It is known that external mechanical forces can regulate structures and functions of living cells tissues in physiology diseases. However, after cessation the force, how are altered response to dynamics chromatin molecules nucleoplasm remains elusive. Here, using single-molecule imaging approaches, we show exogenous local via integrins applied for 2 10 min decondensed increased protein mobility inside nucleus, leading elevated diffusivity single nucleoplasm, tens minutes force. Diffusion experiments with fluorescence correlation spectroscopy live mechanomemory was regulated by nuclear pore complexes. Protein molecular simulation recapitulated experimental findings showed number The force represents a physical process reverses protein–protein condensation phase separation unjamming chromatin. Our suggest effect on nucleus thus more far-reaching than previously anticipated.

Язык: Английский

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Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD

Molecular Neurodegeneration, Год журнала: 2024, Номер 19(1)

Опубликована: Янв. 22, 2024

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders on a disease spectrum that characterized by the cytoplasmic mislocalization aberrant phase transitions of prion-like RNA-binding proteins (RBPs). The common accumulation TAR DNA-binding protein-43 (TDP-43), fused in sarcoma (FUS), other nuclear RBPs detergent-insoluble aggregates cytoplasm degenerating neurons ALS/FTD is connected to pore dysfunction defects nucleocytoplasmic transport machinery. Recent advances suggest beyond their canonical role import protein cargoes, nuclear-import receptors (NIRs) can prevent reverse TDP-43, FUS, related restore localization function. Here, we showcase NIR family how they recognize cargo, drive import, chaperone linked ALS/FTD. We also discuss promise enhancing levels developing potentiated variants as therapeutic strategies for proteinopathies.

Язык: Английский

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Overview of AlphaFold2 and breakthroughs in overcoming its limitations

Computers in Biology and Medicine, Год журнала: 2024, Номер 176, С. 108620 - 108620

Опубликована: Май 15, 2024

Язык: Английский

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AlphaFold two years on: Validation and impact

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(34)

Опубликована: Авг. 12, 2024

Two years on from the initial release of AlphaFold, we have seen its widespread adoption as a structure prediction tool. Here, discuss some latest work based with particular focus use within structural biology community. This encompasses cases like speeding up determination itself, enabling new computational studies, and building tools workflows. We also look at ongoing validation predictions continue to be compared against large numbers experimental structures further delineate model’s capabilities limitations.

Язык: Английский

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Nuclear pore dysfunction and disease: a complex opportunity

Nucleus, Год журнала: 2024, Номер 15(1)

Опубликована: Фев. 21, 2024

The separation of genetic material from bulk cytoplasm has enabled the evolution increasingly complex organisms, allowing for development sophisticated forms life. However, this complexity created new categories dysfunction, including those related to movement between cellular compartments. In eukaryotic cells, nucleocytoplasmic trafficking is a fundamental biological process, and cumulative disruptions nuclear integrity transport are detrimental cell survival. This particularly true in post-mitotic neurons, where pore injury errors strongly associated with neurodegenerative disease. review, we summarize current understanding biology physiological pathological contexts discuss potential therapeutic approaches addressing dysfunctional transport.

Язык: Английский

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