4GZ2

Mus Musculus Tdp2 excluded ssDNA complex

Summary for 4GZ2

• Entry DOI: 10.2210/pdb4gz2/pdb
• Related: 4GYZ 4GZ0 4GZ1
• Descriptor: Tyrosyl-DNA phosphodiesterase 2, DNA (5'-D(*CP*AP*TP*CP*CP*GP*AP*AP*TP*TP*CP*G)-3'), FORMIC ACID, ... (5 entities in total)
• Functional Keywords: protein-dna complex, dna repair, 5'-dna end processing, endonuclease/exonuclease/phosphatase domain, eep domain, 5'-dna end recognition, hydrolase-dna complex, hydrolase/dna
• Biological source: Mus musculus (mouse)
• Total number of polymer chains: 4
• Total formula weight: 64988.03

Authors

Schellenberg, M.J.,Williams, R.S. (deposition date: 2012-09-05, release date: 2012-10-31, Last modification date: 2024-02-28)

Primary citation

Schellenberg, M.J.,Appel, C.D.,Adhikari, S.,Robertson, P.D.,Ramsden, D.A.,Williams, R.S.
Mechanism of repair of 5'-topoisomerase II-DNA adducts by mammalian tyrosyl-DNA phosphodiesterase 2.
Nat.Struct.Mol.Biol., 19:1363-1371, 2012

PubMed Abstract: The topoisomerase II (topo II) DNA incision-and-ligation cycle can be poisoned (for example following treatment with cancer chemotherapeutics) to generate cytotoxic DNA double-strand breaks (DSBs) with topo II covalently conjugated to DNA. Tyrosyl-DNA phosphodiesterase 2 (Tdp2) protects genomic integrity by reversing 5'-phosphotyrosyl-linked topo II-DNA adducts. Here, X-ray structures of mouse Tdp2-DNA complexes reveal that Tdp2 β-2-helix-β DNA damage-binding 'grasp', helical 'cap' and DNA lesion-binding elements fuse to form an elongated protein-DNA conjugate substrate-interaction groove. The Tdp2 DNA-binding surface is highly tailored for engagement of 5'-adducted single-stranded DNA ends and restricts nonspecific endonucleolytic or exonucleolytic processing. Structural, mutational and functional analyses support a single-metal ion catalytic mechanism for the exonuclease-endonuclease-phosphatase (EEP) nuclease superfamily and establish a molecular framework for targeted small-molecule blockade of Tdp2-mediated resistance to anticancer topoisomerase drugs.

PubMed: 23104055
DOI: 10.1038/nsmb.2418

Experimental method

X-RAY DIFFRACTION (1.85 Å)