3L4J

Topoisomerase II-DNA cleavage complex, apo

Summary for 3L4J

• Entry DOI: 10.2210/pdb3l4j/pdb
• Related: 3L4K
• Descriptor: DNA topoisomerase 2, DNA (5'-D(P*CP*CP*TP*AP*CP*TP*GP*CP*TP*AP*C)-3'), DNA (5'-D(*CP*GP*CP*GP*GP*TP*AP*GP*CP*AP*GP*TP*AP*GP*G)-3'), ... (7 entities in total)
• Functional Keywords: topoisomerase, protein-dna complex, covalently linked complex, dna supercoiling, dna replication, atp-binding, dna-binding, isomerase, nucleotide-binding, nucleus, phosphoprotein, isomerase-dna complex, isomerase/dna
• Biological source: Saccharomyces cerevisiae (brewer's yeast,lager beer yeast,yeast)
• Total number of polymer chains: 5
• Total formula weight: 103946.64

Authors

Schmidt, B.H.,Burgin, A.B.,Deweese, J.E.,Osheroff, N.,Berger, J.M. (deposition date: 2009-12-20, release date: 2010-05-26, Last modification date: 2023-11-22)

Primary citation

Schmidt, B.H.,Burgin, A.B.,Deweese, J.E.,Osheroff, N.,Berger, J.M.
A novel and unified two-metal mechanism for DNA cleavage by type II and IA topoisomerases.
Nature, 465:641-644, 2010

PubMed Abstract: Type II topoisomerases are required for the management of DNA tangles and supercoils, and are targets of clinical antibiotics and anti-cancer agents. These enzymes catalyse the ATP-dependent passage of one DNA duplex (the transport or T-segment) through a transient, double-stranded break in another (the gate or G-segment), navigating DNA through the protein using a set of dissociable internal interfaces, or 'gates'. For more than 20 years, it has been established that a pair of dimer-related tyrosines, together with divalent cations, catalyse G-segment cleavage. Recent efforts have proposed that strand scission relies on a 'two-metal mechanism', a ubiquitous biochemical strategy that supports vital cellular processes ranging from DNA synthesis to RNA self-splicing. Here we present the structure of the DNA-binding and cleavage core of Saccharomyces cerevisiae topoisomerase II covalently linked to DNA through its active-site tyrosine at 2.5A resolution, revealing for the first time the organization of a cleavage-competent type II topoisomerase configuration. Unexpectedly, metal-soaking experiments indicate that cleavage is catalysed by a novel variation of the classic two-metal approach. Comparative analyses extend this scheme to explain how distantly-related type IA topoisomerases cleave single-stranded DNA, unifying the cleavage mechanisms for these two essential enzyme families. The structure also highlights a hitherto undiscovered allosteric relay that actuates a molecular 'trapdoor' to prevent subunit dissociation during cleavage. This connection illustrates how an indispensable chromosome-disentangling machine auto-regulates DNA breakage to prevent the aberrant formation of mutagenic and cytotoxic genomic lesions.

PubMed: 20485342
DOI: 10.1038/nature08974

Experimental method

X-RAY DIFFRACTION (2.48 Å)