1lpq
From Proteopedia
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| , resolution 3.14Å | |||||||
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| Activity: | DNA topoisomerase, with EC number 5.99.1.2 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
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. 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
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