1lpq
From Proteopedia
|
Human DNA Topoisomerase I (70 Kda) In Non-Covalent Complex With A 22 Base Pair DNA Duplex Containing an 8-oxoG Lesion
Contents |
Overview
7,8-Dihydro-8-oxoguanine (8-oxoG) is the most common form of oxidative DNA, damage in human cells. Biochemical studies have shown that 8-oxoG, decreases the DNA cleavage activity of human topoisomerase I, an enzyme, vital to DNA metabolism and stability. We present the 3.1-A crystal, structure of human topoisomerase I in noncovalent complex with a DNA, oligonucleotide containing 8-oxoG at the +1 position in the scissile, strand. We find that 8-oxoG reorganizes the active site of human, topoisomerase I into an inactive conformation relative to the structures, of topoisomerase I-DNA complexes elucidated previously. The catalytic, Tyr-723-Phe rotates away from the DNA cleavage site and packs into the, body of the molecule. A second active-site residue, Arg-590, becomes, disordered and is not observed in the structure. The docked, inactive, conformation of Tyr-723-Phe is reminiscent of the related tyrosine, recombinase family of integrases and recombinases, suggesting a common, regulatory mechanism. We propose that human topoisomerase I binds to DNA, first in an inactive conformation and then rearranges its active site for, catalysis. 8-OxoG appears to impact topoisomerase I by stabilizing the, inactive, DNA-bound state.
Disease
Known disease associated with this structure: DNA topoisomerase I, camptothecin-resistant OMIM:[126420]
About this Structure
1LPQ is a Single protein structure of sequence from Homo sapiens. Active as DNA topoisomerase, with EC number 5.99.1.2 Full crystallographic information is available from OCA.
Reference
8-Oxoguanine rearranges the active site of human topoisomerase I., Lesher DT, Pommier Y, Stewart L, Redinbo MR, Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12102-7. Epub 2002 Sep 3. PMID:12209008
Page seeded by OCA on Mon Nov 12 18:03:21 2007
