Download MendeleyCrystal structure of a transition state mimic for Tdp1 assembled from vanadate, DNA, and a topoisomerase I-derived peptide
Davies, D.R., Interthal, H., Champoux, J.J., Hol, W.G.J.(2003) Chem Biol 10: 139-147
- PubMed: 12618186
- DOI: https://doi.org/10.1016/s1074-5521(03)00021-8
- Primary Citation of Related Structures:
1NOP - PubMed Abstract:
Tyrosyl-DNA phosphodiesterase (Tdp1) is a member of the phospholipase D superfamily and acts as a DNA repair enzyme that removes stalled topoisomerase I- DNA complexes by hydrolyzing the bond between a tyrosine side chain and a DNA 3' phosphate. Despite the complexity of the substrate of this phosphodiesterase, vanadate succeeded in linking human Tdp1, a tyrosine-containing peptide, and a single-stranded DNA oligonucleotide into a quaternary complex that mimics the transition state for the first step of the catalytic reaction. The conformation of the bound substrate mimic gives compelling evidence that the topoisomerase I-DNA complex must undergo extensive modification prior to cleavage by Tdp1. The structure also illustrates that the use of vanadate as the central moiety in high-order complexes has the potential to be a general method for capturing protein-substrate interactions for phosphoryl transfer enzymes, even when the substrates are large, complicated, and unusual.
Organizational Affiliation:
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
