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A FluoPol-ABPP PAD2 high-throughput screen identifies the first calcium site inhibitor targeting the PADs

Academic Article
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Overview

authors

  • Lewallen, D. M.
  • Bicker, K. L.
  • Madoux, F.
  • Chase, P.
  • Anguish, L.
  • Coonrod, S.
  • Hodder, Peter
  • Thompson, Paul

publication date

  • April 2014

journal

  • ACS Chemical Biology  Journal

abstract

  • The protein arginine deiminases (PADs) catalyze the post-translational hydrolysis of peptidyl-arginine to form peptidyl-citrulline in a process termed deimination or citrullination. PADs likely play a role in the progression of a range of disease states because dysregulated PAD activity is observed in a host of inflammatory diseases and cancer. For example, recent studies have shown that PAD2 activates ERα target gene expression in breast cancer cells by citrullinating histone H3 at ER target promoters. To date, all known PAD inhibitors bind directly to the enzyme active site. PADs, however, also require calcium ions to drive a conformational change between the inactive apo-state and the fully active calcium bound holoenzyme, suggesting that it would be possible to identify inhibitors that bind the apoenzyme and prevent this conformational change. As such, we set out to develop a screen that can identify PAD2 inhibitors that bind to either the apo or calcium bound form of PAD2. Herein, we provide definitive proof of concept for this approach and report the first PAD inhibitor, ruthenium red (Ki of 17 μM), to preferentially bind the apoenzyme.

subject areas

  • Binding Sites
  • Biological Assay
  • Calcium
  • Drug Delivery Systems
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors
  • Hydrolases
  • Molecular Structure
  • Protein Binding
  • Ruthenium Red
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Identity

PubMed Central ID

  • PMC4108211

International Standard Serial Number (ISSN)

  • 1554-8929

Digital Object Identifier (DOI)

  • 10.1021/cb400841k

PubMed ID

  • 24467619
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Additional Document Info

start page

  • 913

end page

  • 921

volume

  • 9

issue

  • 4

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