Survey of phosphorylation near drug binding sites in the Protein Data Bank (PDB) and their effects

Kyle P. Smith, Kathleen M. Gifford, Joshua S. Waitzman, Sarah E. Rice*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


While it is currently estimated that 40 to 50% of eukaryotic proteins are phosphorylated, little is known about the frequency and local effects of phosphorylation near pharmaceutical inhibitor binding sites. In this study, we investigated how frequently phosphorylation may affect the binding of drug inhibitors to target proteins. We examined the 453 non-redundant structures of soluble mammalian drug target proteins bound to inhibitors currently available in the Protein Data Bank (PDB). We cross-referenced these structures with phosphorylation data available from the PhosphoSitePlus database. Three hundred twenty-two of 453 (71%) of drug targets have evidence of phosphorylation that has been validated by multiple methods or labs. For 132 of 453 (29%) of those, the phosphorylation site is within 12 Å of the small molecule-binding site, where it would likely alter small molecule binding affinity. We propose a framework for distinguishing between drug-phosphorylation site interactions that are likely to alter the efficacy of drugs versus those that are not. In addition we highlight examples of well-established drug targets, such as estrogen receptor alpha, for which phosphorylation may affect drug affinity and clinical efficacy. Our data suggest that phosphorylation may affect drug binding and efficacy for a significant fraction of drug target proteins.

Original languageEnglish (US)
Pages (from-to)25-36
Number of pages12
JournalProteins: Structure, Function and Bioinformatics
Issue number1
StatePublished - Jan 2015


  • Binding affinity
  • Crystal structure
  • Data mining
  • Drug target
  • Inhibitor
  • Ligand
  • PhosphoSitePlus

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology


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