Survey of phosphorylation near drug binding sites in the Protein Data Bank (PDB) and their effects
Citations Over TimeTop 10% of 2014 papers
Abstract
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.
Related Papers
- → Protein Data Bank (PDB): Database of Three-Dimensional Structural Information of Biological Macromolecules(1998)767 cited
- → Intrinsic Disorder in the Protein Data Bank(2007)171 cited
- → BioJava-ModFinder: identification of protein modifications in 3D structures from the Protein Data Bank(2017)10 cited
- → Using the Tools and Resources of the RCSB Protein Data Bank(2016)10 cited
- → The Protein Data Bank ( PDB ) and Macromolecular Structure Data Supporting Computer‐Aided Drug Design(2023)4 cited