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A computational method for detection of ligand-binding proteins from dose range thermal proteome profiles

Detecting ligand-protein interactions in living cells is a fundamental challenge in molecular biology and drug research. Proteome-wide profiling of thermal stability as a function of ligand concentration promises to tackle this challenge. However, current data analysis strategies use preset threshol...

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Bibliographic Details
Main Authors: Kurzawa, Nils (Author) , Becher, Isabelle (Author) , Sridharan, Sindhuja (Author) , Franken, Holger (Author) , Mateus, André (Author) , Anders, Simon (Author) , Bantscheff, Marcus (Author) , Huber, Wolfgang (Author) , Savitski, Mikhail M. (Author)
Format: Article (Journal)
Language:English
Published: 13 November 2020
In: Nature Communications
Year: 2020, Volume: 11
ISSN:2041-1723
DOI:10.1038/s41467-020-19529-8
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41467-020-19529-8
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41467-020-19529-8
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Author Notes:Nils Kurzawa, Isabelle Becher, Sindhuja Sridharan, Holger Franken, André Mateus, Simon Anders, Marcus Bantscheff, Wolfgang Huber & Mikhail M. Savitski
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Summary:Detecting ligand-protein interactions in living cells is a fundamental challenge in molecular biology and drug research. Proteome-wide profiling of thermal stability as a function of ligand concentration promises to tackle this challenge. However, current data analysis strategies use preset thresholds that can lead to suboptimal sensitivity/specificity tradeoffs and limited comparability across datasets. Here, we present a method based on statistical hypothesis testing on curves, which provides control of the false discovery rate. We apply it to several datasets probing epigenetic drugs and a metabolite. This leads us to detect off-target drug engagement, including the finding that the HDAC8 inhibitor PCI-34051 and its analog BRD-3811 bind to and inhibit leucine aminopeptidase 3. An implementation is available as an R package from Bioconductor (https://bioconductor.org/packages/TPP2D). We hope that our method will facilitate prioritizing targets from thermal profiling experiments.
Item Description:Gesehen am 15.01.2021
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-020-19529-8

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