Structural basis for recognition of 5'-phosphotyrosine adducts by Tdp2

Nat Struct Mol Biol. 2012 Dec;19(12):1372-7. doi: 10.1038/nsmb.2423. Epub 2012 Oct 28.


The DNA-repair enzyme Tdp2 resolves 5'-phosphotyrosyl DNA adducts and mediates resistance to anticancer drugs that target covalent topoisomerase-DNA complexes. Tdp2 also participates in key signaling pathways during development and tumorigenesis and cleaves a protein-RNA linkage during picornavirus replication. The crystal structure of zebrafish Tdp2 bound to DNA reveals a deep, narrow basic groove that selectively accommodates the 5' end of single-stranded DNA in a stretched conformation. The crystal structure of the full-length Caenorhabditis elegans Tdp2 shows that this groove can also accommodate an acidic peptide stretch in vitro, with glutamate and aspartate side chains occupying the DNA backbone phosphate-binding sites. This extensive molecular mimicry suggests a potential mechanism for autoregulation and interaction of Tdp2 with phosphorylated proteins in signaling. Our study provides a framework to interrogate functions of Tdp2 and develop inhibitors for chemotherapeutic and antiviral applications.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • DNA-Binding Proteins
  • Humans
  • Models, Molecular
  • Nuclear Proteins / chemistry*
  • Nuclear Proteins / metabolism
  • Phosphoric Diester Hydrolases
  • Phosphotyrosine / chemistry*
  • Signal Transduction
  • Transcription Factors / chemistry*
  • Transcription Factors / metabolism
  • Zebrafish


  • DNA-Binding Proteins
  • Nuclear Proteins
  • Transcription Factors
  • Phosphotyrosine
  • Phosphoric Diester Hydrolases
  • TDP2 protein, human

Associated data

  • PDB/4F1H
  • PDB/4F1I
  • PDB/4FPV
  • PDB/4FVA
  • PDB/4GEW