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Proteome-wide covalent ligand discovery in native biological systems

Academic Article
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Overview

related to degree

  • Lum, Kenneth, Ph.D. in Chemical Biology, Scripps Research 2013 - 2018
  • Lanning, Bryan, Ph.D. in Chemical Biology, Scripps Research 2011 - 2016
  • Chatterjee, Sandip, Ph.D. in Chemical Biology, Scripps Research 2010 - 2015

authors

  • Backus, K. M.
  • Correia, B. E.
  • Lum, Kenneth
  • Forli, Stefano
  • Horning, B. D.
  • Gonzalez-Paez, G. E.
  • Chatterjee, Sandip
  • Lanning, Bryan
  • Teijaro, John R.
  • Olson, Arthur
  • Wolan, Dennis
  • Cravatt, Benjamin

publication date

  • June 2016

journal

  • Nature  Journal

abstract

  • Small molecules are powerful tools for investigating protein function and can serve as leads for new therapeutics. Most human proteins, however, lack small-molecule ligands, and entire protein classes are considered 'undruggable'. Fragment-based ligand discovery can identify small-molecule probes for proteins that have proven difficult to target using high-throughput screening of complex compound libraries. Although reversibly binding ligands are commonly pursued, covalent fragments provide an alternative route to small-molecule probes, including those that can access regions of proteins that are difficult to target through binding affinity alone. Here we report a quantitative analysis of cysteine-reactive small-molecule fragments screened against thousands of proteins in human proteomes and cells. Covalent ligands were identified for >700 cysteines found in both druggable proteins and proteins deficient in chemical probes, including transcription factors, adaptor/scaffolding proteins, and uncharacterized proteins. Among the atypical ligand-protein interactions discovered were compounds that react preferentially with pro- (inactive) caspases. We used these ligands to distinguish extrinsic apoptosis pathways in human cell lines versus primary human T cells, showing that the former is largely mediated by caspase-8 while the latter depends on both caspase-8 and -10. Fragment-based covalent ligand discovery provides a greatly expanded portrait of the ligandable proteome and furnishes compounds that can illuminate protein functions in native biological systems.

subject areas

  • Apoptosis
  • Caspase 10
  • Caspase 8
  • Cells, Cultured
  • Cysteine
  • Drug Evaluation, Preclinical
  • Enzyme Precursors
  • Humans
  • Ligands
  • Peptide Fragments
  • Proteome
  • Small Molecule Libraries
  • T-Lymphocytes
  • Transcription Factors
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Identity

PubMed Central ID

  • PMC4919207

International Standard Serial Number (ISSN)

  • 0028-0836

Digital Object Identifier (DOI)

  • 10.1038/nature18002

PubMed ID

  • 27309814
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Additional Document Info

start page

  • 570

end page

  • 574

volume

  • 534

issue

  • 7608

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