The importance of protein domain mutations in cancer therapy DOI Creative Commons
Kiran Kumar Chitluri, Isaac Arnold Emerson

Heliyon, Journal Year: 2024, Volume and Issue: 10(6), P. e27655 - e27655

Published: March 1, 2024

Cancer is a complex disease that caused by multiple genetic factors. Researchers have been studying protein domain mutations to understand how they affect the progression and treatment of cancer. These can significantly impact development spread cancer changing structure, function, signalling pathways. As result, there growing interest in these be used as prognostic indicators for prognosis. Recent studies shown provide valuable information about severity patient's response treatment. They may also predict resistance targeted therapy The clinical implications are significant, regarded essential biomarkers oncology. However, additional techniques approaches required characterize changes domains their functional effects. Machine learning other computational tools offer promising solutions this challenge, enabling prediction on structure function. Such predictions aid interpretation information. Furthermore, genome editing like CRISPR/Cas9 has made it possible validate significance mutants more efficiently accurately. In conclusion, hold great promise predictive Overall, considerable research still needed better define molecular heterogeneity resolve challenges remain, so full potential realized.

Language: Английский

Integrative spatiotemporal modeling of biomolecular processes: Application to the assembly of the nuclear pore complex DOI Creative Commons
Andrew P. Latham, Wanlu Zhang, Jeremy O. B. Tempkin

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(11)

Published: March 14, 2025

Dynamic processes involving biomolecules are essential for the function of cell. Here, we introduce an integrative method computing models these based on multiple heterogeneous sources information, including time-resolved experimental data and physical dynamic processes. First, each time point, a set coarse compositional structural heterogeneity is computed (heterogeneity models). Second, model, static structure (a snapshot model). Finally, selected connected into series trajectories that optimize likelihood both transitions between them trajectory The demonstrated by application to assembly process human nuclear pore complex in context reforming envelope during mitotic cell division, live-cell correlated electron tomography, bulk fluorescence correlation spectroscopy–calibrated quantitative live imaging, model fully assembled complex. Modeling improves precision over modeling alone. applicable wide range time-dependent systems biology available broader scientific community through implementation open source Integrative Platform (IMP) software.

Language: Английский

Citations

1
Improved Proteomics-Based Drug Mechanism-of-Action Studies Using 16-Plex Isobaric Mass Tags DOI
Nico Zinn, Thilo Werner,

Carola Doce

et al.

Journal of Proteome Research, Journal Year: 2021, Volume and Issue: 20(3), P. 1792 - 1801

Published: Feb. 23, 2021

Multiplexed quantitative proteomics enabled complex workflows to study the mechanisms by which small molecule drugs interact with proteome such as thermal profiling (TPP) or multiplexed dynamics (mPDP). TPP measures changes in protein stability response drug treatment and thus informs on direct targets downstream regulation events, while mPDP approach enables discovery of regulated synthesis degradation events caused molecules other perturbations. The isobaric mass tags available for have far limited efficiency sensitivity experiments could be performed. Here we evaluate a recent generation 16-plex demonstrate sensitive time efficient identification Staurosporine HepG2 cell extracts recording full denaturation/aggregation profiles vehicle compound treated samples single spectrometry experiment. In 2D-TPP experiments, isothermal titration over seven concentrations per temperature comprehensive selectivity EC50 values kinase tightly matching kinobeads gold standard assay. Finally, condition-based multiplexing dynamic SILAC labeling delineate proteome-wide effects molecular glue Indisulam rates.

Language: Английский

Citations

43
Neuron-specific protein network mapping of autism risk genes identifies shared biological mechanisms and disease-relevant pathologies DOI
Nadeem Murtaza,

Annie A. Cheng,

Chad O. Brown

et al.

Cell Reports, Journal Year: 2022, Volume and Issue: 41(8), P. 111678 - 111678

Published: Nov. 1, 2022

Language: Английский

Citations

34
Multiplexed kinase interactome profiling quantifies cellular network activity and plasticity DOI Creative Commons
Martin Golkowski,

Andrea Lius,

Tanmay Sapre

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(5), P. 803 - 818.e8

Published: Feb. 2, 2023

Language: Английский

Citations

22
Proteomic approaches advancing targeted protein degradation DOI Creative Commons
Gajanan Sathe, Gopal P. Sapkota

Trends in Pharmacological Sciences, Journal Year: 2023, Volume and Issue: 44(11), P. 786 - 801

Published: Sept. 29, 2023

Targeted protein degradation (TPD) is an emerging modality for research and therapeutics. Most TPD approaches harness cellular ubiquitin-dependent proteolytic pathways. Proteolysis-targeting chimeras (PROTACs) molecular glue (MG) degraders (MGDs) represent the most advanced approaches, with some already used in clinical settings. Despite these advances, still faces many challenges, pertaining to both development of effective, selective, tissue-penetrant understanding their mode action. In this review, we focus on progress made addressing challenges. particular, discuss utility application recent proteomic as indispensable tools enable insights into degrader development, including target engagement, selectivity, efficacy, safety,

Language: Английский

Citations

22
Advance computational tools for multiomics data learning DOI
Sheikh Mansoor,

Saira Hamid,

Thai Thanh Tuan

et al.

Biotechnology Advances, Journal Year: 2024, Volume and Issue: 77, P. 108447 - 108447

Published: Sept. 7, 2024

Language: Английский

Citations

8
Protein mimetic 2D FAST rescues alpha synuclein aggregation mediated early and post disease Parkinson’s phenotypes DOI Creative Commons
Nicholas H. Stillman,

Johnson A Joseph,

Jemil Ahmed

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: April 30, 2024

Abstract Abberent protein-protein interactions potentiate many diseases and one example is the toxic, self-assembly of α-Synuclein in dopaminergic neurons patients with Parkinson’s disease; therefore, a potential therapeutic strategy small molecule modulation aggregation. In this work, we develop an Oligopyridylamide based 2-dimensional Fragment-Assisted Structure-based Technique to identify antagonists The technique utilizes fragment-based screening extensive array non-proteinogenic side chains Oligopyridylamides, leading identification NS132 as antagonist multiple facets We further more cell permeable analog (NS163) without sacrificing activity. Oligopyridylamides rescue aggregation mediated disease phenotypes early post Caenorhabditis elegans models. forsee tremendous our lead therapeutics for other it expandable oligoamide scaffolds larger chains.

Language: Английский

Citations

6
Chemical cross-linking and mass spectrometry enabled systems-level structural biology DOI
Luke Botticelli, Anna Bakhtina,

Nathan K. Kaiser

et al.

Current Opinion in Structural Biology, Journal Year: 2024, Volume and Issue: 87, P. 102872 - 102872

Published: June 26, 2024

Language: Английский

Citations

6
A biotin targeting chimera (BioTAC) system to map small molecule interactomes in situ DOI Creative Commons
Andrew J. Tao, Jiewei Jiang, Gillian E. Gadbois

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Dec. 4, 2023

Abstract Understanding how small molecules bind to specific protein complexes in living cells is critical understanding their mechanism-of-action. Unbiased chemical biology strategies for direct readout of interactome remodelling by would provide advantages over target-focused approaches, including the ability detect previously unknown ligand targets and complexes. However, there are few current methods unbiased profiling molecule interactomes. To address this, we envisioned a technology that combine sensitivity live-cell compatibility proximity labelling coupled mass spectrometry, with specificity nature chemoproteomics. In this manuscript, describe BioTAC system, small-molecule guided platform can rapidly identify both complexed binding proteins. We benchmark system against µMap, photoaffinity labelling, affinity purification spectrometry datasets. also apply maps Trametinib analogues. The overcomes limitation approaches supports identification inhibitor bound molecular glue

Language: Английский

Citations

16
Comparison of two peroxidases with high potential for biotechnology applications – HRP vs. APEX2 DOI Creative Commons

Sanja Škulj,

Matej Kožić,

Antun Barišić

et al.

Computational and Structural Biotechnology Journal, Journal Year: 2024, Volume and Issue: 23, P. 742 - 751

Published: Jan. 18, 2024

Peroxidases are essential elements in many biotechnological applications. An especially interesting concept involves split enzymes, where the enzyme is separated into two smaller and inactive proteins that can dimerize a fully active enzyme. Such forms were developed for horseradish peroxidase (HRP) ascorbate (APX) already. Both peroxidases have high potential biotechnology In present study, we performed biophysical comparisons of these their analogues. The site availability similar all four structures. enzymes comparable stability with native analogues, meaning they be used further Also, tertiary structures similar. However, differences might help choosing one system over another applications noticed. main difference between systems glycosylation which not case APX/sAPEX2, while it has impact on HRP/sHRP stability. Further calcium ions cysteine bridges only HRP/sHRP. Finally, computational results identified sAPEX2 as smallest structural variations during molecular dynamics simulations showing its dominant comparing to other simulated proteins. Taken together, due lack glycans cysteines, well

Language: Английский

Citations

5