Improved drug target deconvolution with PISA-DIA using an extended, overlapping temperature gradient.
Proteome Integral Solubility Alteration
data independent acquisition (DIA)
mass spectrometry
protein stability
proteomics
target engagement
thermal proteome profiling
Journal
Proteomics
ISSN: 1615-9861
Titre abrégé: Proteomics
Pays: Germany
ID NLM: 101092707
Informations de publication
Date de publication:
20 May 2024
20 May 2024
Historique:
revised:
03
05
2024
received:
19
12
2023
accepted:
07
05
2024
medline:
20
5
2024
pubmed:
20
5
2024
entrez:
20
5
2024
Statut:
aheadofprint
Résumé
Thermal proteome profiling (TPP) is a powerful tool for drug target deconvolution. Recently, data-independent acquisition mass spectrometry (DIA-MS) approaches have demonstrated significant improvements to depth and missingness in proteome data, but traditional TPP (a.k.a. CEllular Thermal Shift Assay "CETSA") workflows typically employ multiplexing reagents reliant on data-dependent acquisition (DDA). Herein, we introduce a new experimental design for the Proteome Integral Solubility Alteration via label-free DIA approach (PISA-DIA). We highlight the proteome coverage and sensitivity achieved by using multiple overlapping thermal gradients alongside DIA-MS, which maximizes efficiencies in PISA sample concatenation and safeguards against missing protein targets that exist at high melting temperatures. We demonstrate our extended PISA-DIA design has superior proteome coverage as compared to using tandem-mass tags (TMT) necessitating DDA-MS analysis. Importantly, we demonstrate our PISA-DIA approach has the quantitative and statistical rigor using A-1331852, a specific inhibitor of BCL-xL. Due to the high melt temperature of this protein target, we utilized our extended multiple gradient PISA-DIA workflow to identify BCL-xL. We assert our novel overlapping gradient PISA-DIA-MS approach is ideal for unbiased drug target deconvolution, spanning a large temperature range whilst minimizing target dropout between gradients, increasing the likelihood of resolving the protein targets of novel compounds.
Identifiants
pubmed: 38766901
doi: 10.1002/pmic.202300644
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e2300644Informations de copyright
© 2024 The Authors. Proteomics published by Wiley‐VCH GmbH.
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