PDBsum entry: 1seu

Isomerase/DNA

PDB id: 1seu

Contents

Protein chain

565 a.a. *

DNA/RNA

Ligands

SA3

* Residue conservation analysis

PDB id:

1seu

Name:

Isomerase/DNA

Title:

Human DNA topoisomerase i (70 kda) in complex with the indolocarbazole sa315f and covalent complex with a 22 base pair DNA duplex

Structure:

5'-d( Ap Ap Ap Ap Ap Gp Ap Cp Tp T)-3'. Chain: b. Engineered: yes. 5'-d( (Tgp)p Gp Ap Ap Ap Ap Ap Tp Tp Tp Tp T)-3'. Chain: c. Engineered: yes. 5'- d( Ap Ap Ap Ap Ap Tp Tp Tp Tp Tp Cp Cp Ap Ap Gp Tp Cp Tp Tp Tp Tp T)-3'.

Source:

Synthetic: yes. Homo sapiens. Human. Organism_taxid: 9606. Gene: top1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Biol. unit:

Tetramer (from PQS)

Resolution:

3.00Å R-factor: 0.237 R-free: 0.295

Authors:

B.L.Staker,M.D.Feese,M.Cushman,Y.Pommier,D.Zembower, L.Stewart,A.B.Burgin

Key ref:

B.L.Staker et al. (2005). Structures of three classes of anticancer agents bound to the human topoisomerase I-DNA covalent complex. J Med Chem, 48, 2336-2345. PubMed id: 15801827 DOI: 10.1021/jm049146p

Date:

18-Feb-04 Release date: 19-Apr-05

Protein chain

P11387  (TOP1_HUMAN) -  DNA topoisomerase 1

Seq: 765 a.a.

Struc: 565 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.5.99.1.2 - Dna topoisomerase.
• Reaction: ATP-independent breakage of single-stranded DNA, followed by passage and rejoining.

 Gene Ontology (GO) functional annotation 

• Cellular component: chromosome (1 term)
• Biological process: DNA topological change (2 terms)
• Biochemical function: DNA binding (3 terms)

DOI no: 10.1021/jm049146p

J Med Chem 48:2336-2345 (2005)

PubMed id: 15801827

Structures of three classes of anticancer agents bound to the human topoisomerase I-DNA covalent complex.

B.L.Staker, M.D.Feese, M.Cushman, Y.Pommier, D.Zembower, L.Stewart, A.B.Burgin.

ABSTRACT

Human topoisomerase I (top1) is the molecular target of a diverse set of anticancer compounds, including the camptothecins, indolocarbazoles, and indenoisoquinolines. These compounds bind to a transient top1-DNA covalent complex and inhibit the resealing of a single-strand nick that the enzyme creates to relieve superhelical tension in duplex DNA. (Hertzberg, R. P.; et al. Biochem. 1989, 28, 4629-4638. Hsiang, Y. H.; et al. J. Biol. Chem 1985, 260, 14873-14878. Champoux, J. J. Annu. Rev. Biochem. 2001, 70, 369-413. Stewart, L.; et al. Science 1998, 729, 1534-1541.) We report the X-ray crystal structures of the human top1-DNA complex bound with camptothecin and representative members of the indenoisoquinoline and indolocarbazole classes of top1 poisons. The planar nature of all three structurally diverse classes allows them to intercalate between DNA base pairs at the site of single-strand cleavage. All three classes of compounds have a free electron pair near Arg364, a residue that if mutated confers resistance to all three classes of drugs. The common intercalative binding mode is augmented by unexpected chemotype-specific contacts with amino acid residues Asn352 and Glu356, which adopt alternative side-chain conformations to accommodate the bound compounds. These new X-ray structures explain how very different molecules can stabilize top1-DNA covalent complexes and will aid the rational design of completely novel structural classes of anticancer drugs.