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1ej9
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(New page: 200px<br /> <applet load="1ej9" size="450" color="white" frame="true" align="right" spinBox="true" caption="1ej9, resolution 2.6Å" /> '''CRYSTAL STRUCTURE OF...)
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Revision as of 14:37, 12 November 2007
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CRYSTAL STRUCTURE OF HUMAN TOPOISOMERASE I DNA COMPLEX
Contents |
Overview
Human topoisomerase I helps to control the level of DNA supercoiling in, cells and is vital for numerous DNA metabolic events, including, replication, transcription, and recombination. The 2.6 A crystal structure, of human topoisomerase I in noncovalent complex with a DNA duplex, containing a cytosine at the -1 position of the scissile strand rather, than the favored thymine is reported. The hydrogen bond between the O2, position of this -1 base and the epsilon-amino of the conserved Lys-532, residue, the only base-specific contact observed previously in the human, topoisomerase I-DNA interaction, is maintained in this complex. Several, unique features of this structure, however, have implications for the, DNA-binding and active-site mechanisms of the enzyme. First, the ends of, the DNA duplex were observed to shift by up to 5.4 A perpendicular to the, DNA helical axis relative to structures reported previously, suggesting a, novel degree of plasticity in the interaction between human topoisomerase, I and its DNA substrate. Second, 12 additional residues at the NH(2), terminus of the protein (Trp-203-Gly-214) could be built in this, structure, and they were found to pack against the putative hinge region, implicated in the clamping of the enzyme around duplex DNA. Third, a water, molecule was observed adjacent to the scissile phosphate and the, active-site residues; the potential specific base character of this, solvent molecule in the active-site mechanism of the enzyme is discussed., Fourth, the scissile phosphate group was found to be rotated by 75, degrees, bringing Lys-532 into hydrogen-bonding distance of one of the, nonbridging phosphate oxygens. This orientation of the scissile phosphate, group implicates Lys-532 as a fifth active-site residue, and also mimics, the orientation observed for the 3'-phosphotyrosine linkage in the, covalent human topoisomerase I-DNA complex structure. The implications of, these structural features for the mechanism of the enzyme are discussed, including the potential requirement for a rotation of the scissile, phosphate group during DNA strand cleavage and covalent attachment.
Disease
Known disease associated with this structure: DNA topoisomerase I, camptothecin-resistant OMIM:[126420]
About this Structure
1EJ9 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
Novel insights into catalytic mechanism from a crystal structure of human topoisomerase I in complex with DNA., Redinbo MR, Champoux JJ, Hol WG, Biochemistry. 2000 Jun 13;39(23):6832-40. PMID:10841763
Page seeded by OCA on Mon Nov 12 16:43:56 2007
