1RH0: Crystal Structure Of Human Tyrosyl-Dna Phosphodiesterase Complexed With Vanadate, Octopamine And Trinucleotide Gtt

Tyrosyl-DNA phosphodiesterase (Tdp1) catalyzes the hydrolysis of a phosphodiester bond between a tyrosine residue and a DNA 3' phosphate and functions as a DNA repair enzyme that cleaves stalled topoisomerase I-DNA complexes. We previously determined a procedure to crystallize a quaternary complex containing Tdp1, vanadate, a DNA oligonucleotide, and a tyrosine-containing peptide that mimics the transition state for hydrolysis of the Tdp1 substrate. Here, the ability of vanadate to accept a variety of different ligands is exploited to produce several different quaternary complexes with a variety of oligonucleotides, and peptides or a tyrosine analogue, in efforts to explore the binding properties of the Tdp1 DNA and peptide binding clefts. Eight crystal structures of Tdp1 with vanadate, oligonucleotides, and peptides or peptide analogues were determined. These structures demonstrated that Tdp1 is able to bind substituents with limited sequence variation in the polypeptide moiety and also bind oligonucleotides with sequence variation at the 3' end. Additionally, the tyrosine analogue octopamine can replace topoisomerase I derived peptides as the apical ligand to vanadate. The versatility of this system suggests that the formation of quaternary complexes around vanadate could be adapted to become a useful method for structure-based inhibitor design and has the potential to be generally applicable to other enzymes that perform chemistry on phosphate esters.
PDB ID: 1RH0Download
MMDB ID: 51161
PDB Deposition Date: 2003/11/13
Updated in MMDB: 2012/12
Experimental Method:
x-ray diffraction
Resolution: 2.3  Å
Source Organism:
synthetic construct
Similar Structures:
Biological Unit for 1RH0: dimeric; determined by author
Molecular Components in 1RH0
Label Count Molecule
Protein (1 molecule)
Tyrosyl-dna Phosphodiesterase 1(Gene symbol: TDP1)
Molecule annotation
Nucleotide(1 molecule)
Molecule annotation
Chemicals (3 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB