2iuw

From Proteopedia

Revision as of 16:12, 5 November 2007

CRYSTAL STRUCTURE OF HUMAN ABH3 IN COMPLEX WITH IRON ION AND 2-OXOGLUTARATE

Overview

Methylating agents are ubiquitous in the environment, and central in, cancer therapy. The 1-methyladenine and 3-methylcytosine lesions in, DNA/RNA contribute to the cytotoxicity of such agents. These lesions are, directly reversed by ABH3 (hABH3) in humans and AlkB in Escherichia coli., Here, we report the structure of the hABH3 catalytic core in complex with, iron and 2-oxoglutarate (2OG) at 1.5 A resolution and analyse key, site-directed mutants. The hABH3 structure reveals the beta-strand, jelly-roll fold that coordinates a catalytically active iron centre by a, conserved His1-X-Asp/Glu-X(n)-His2 motif. This experimentally establishes, hABH3 as a structural member of the Fe(II)/2OG-dependent dioxygenase, superfamily, which couples substrate oxidation to conversion of 2OG into, succinate and CO2. A positively charged DNA/RNA binding groove indicates a, distinct nucleic acid binding conformation different from that predicted, in the AlkB structure with three nucleotides. These results uncover, previously unassigned key catalytic residues, identify a flexible hairpin, involved in nucleotide flipping and ss/ds-DNA discrimination, and reveal, self-hydroxylation of an active site leucine that may protect against, uncoupled generation of dangerous oxygen radicals.

About this Structure

2IUW is a Single protein structure of sequence from Homo sapiens with FE, AKG and BME as ligands. Structure known Active Site: AC1. Full crystallographic information is available from OCA.

Reference

Human ABH3 structure and key residues for oxidative demethylation to reverse DNA/RNA damage., Sundheim O, Vagbo CB, Bjoras M, Sousa MM, Talstad V, Aas PA, Drablos F, Krokan HE, Tainer JA, Slupphaug G, EMBO J. 2006 Jul 26;25(14):3389-97. Epub 2006 Jul 6. PMID:16858410

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