1RG2

Crystal structure of human Tyrosyl-DNA Phosphodiesterase complexed with vanadate, octopamine, and tetranucleotide AGTA

Summary for 1RG2

• Entry DOI: 10.2210/pdb1rg2/pdb
• Related: 1JY1 1NOP 1RFF 1RFI 1RG1 1RGT 1RGU 1RH0
• Descriptor: 5'-D(*AP*GP*TP*A)-3', Tyrosyl-DNA phosphodiesterase 1, VANADATE ION, ... (7 entities in total)
• Functional Keywords: protein-dna complex, vanadate complex, transition state mimic, hydrolase-dna complex, hydrolase/dna
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: Q9NUW8
• Total number of polymer chains: 4
• Total formula weight: 112937.03

Authors

Davies, D.R.,Interthal, H.,Champoux, J.J.,Hol, W.G. (deposition date: 2003-11-11, release date: 2004-03-02, Last modification date: 2023-08-23)

Primary citation

Davies, D.R.,Interthal, H.,Champoux, J.J.,Hol, W.G.
Explorations of peptide and oligonucleotide binding sites of tyrosyl-DNA phosphodiesterase using vanadate complexes.
J.Med.Chem., 47:829-837, 2004

PubMed Abstract: 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.

PubMed: 14761185
DOI: 10.1021/jm030487x

Experimental method

X-RAY DIFFRACTION (2.1 Å)