Topoisomerase II - drug interaction domains: identification of substituents on etoposide that interact with the enzyme.

Topoisomerase II - drug interaction domains: identification of substituents on etoposide that interact with the enzyme. Research Abstract Details 

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Topoisomerase II - drug interaction domains: identification of substituents on etoposide that interact with the enzyme. Abstract Text:

Amy M Wilstermann,Ryan P Bender,Murrell Godfrey,Sungjo Choi,Clemens Anklin,David B Berkowitz,Neil Osheroff,David E Graves,

Etoposide is one of the most successful chemotherapeutic agents used for the treatment of human cancers. The drug kills cells by inhibiting the ability of topoisomerase II to ligate nucleic acids that it cleaves during the double-stranded DNA passage reaction. Etoposide is composed of a polycyclic ring system (rings A-D), a glycosidic moiety at the C4 position, and a pendent ring (E-ring) at the C1 position. Although drug-enzyme contacts, as opposed to drug-DNA interactions, mediate the entry of etoposide into the topoisomerase II-drug-DNA complex, the substituents on etoposide that interact with the enzyme have not been identified. Therefore, saturation transfer difference [1H]-nuclear magnetic resonance spectroscopy and protein-drug competition binding assays were employed to define the groups on etoposide that associate with yeast topoisomerase II and human topoisomerase IIalpha. Results indicate that the geminal protons of the A-ring, the H5 and H8 protons of the B-ring, and the H2' and H6' protons and the 3'- and 5'-methoxyl protons of the pendent E-ring interact with both enzymes in the binary protein-ligand complexes. In contrast, no significant nuclear Overhauser enhancement signals arising from the C-ring, the D-ring, or the C4 glycosidic moiety were observed with either enzyme, suggesting that there is limited or no contact between these portions of etoposide and topoisomerase II in the binary complex. The functional importance of E-ring substituents was confirmed by topoisomerase II-mediated DNA cleavage assays.

Topoisomerase II - drug interaction domains: identification of substituents on etoposide that interact with the enzyme. Publishing Authors By Initials

AM Wilstermann,RP Bender,M Godfrey,S Choi,C Anklin,DB Berkowitz,N Osheroff,DE Graves,

For similar biochemical phenomena, metabolism, and nutrition: biochemical phenomena: molecular structure: molecular conformation: protein conformation: protein structure, tertiary research abstracts see: biochemical phenomena, metabolism, and nutrition: biochemical phenomena: molecular structure: molecular conformation: protein conformation: protein structure, tertiary research

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Topoisomerase II - drug interaction domains: identification of substituents on etoposide that interact with the enzyme. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Biochemistry

VOLUME: 46

Page Numbers: 8217-25

Journal Abbreviation: Biochemistry

ISSN: 0006-2960

DAY: 20

MONTH: 06

YEAR: 2007

Topoisomerase II - drug interaction domains: identification of substituents on etoposide that interact with the enzyme. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 370623

Topoisomerase II - drug interaction domains: identification of substituents on etoposide that interact with the enzyme. Keywords Mesh Terms:

KEYWORDS: Protein Structure, Tertiary

MESH TERMS: chemistry

Chemical & Substance for Abstract: Topoisomerase II - drug interaction domains: identification of substituents on etoposide that interact with the enzyme. Information

Substance Name: DNA topoisomerase II alpha

Registry Number: EC 5.99.1.3

Grant and Affiliation Information for Topoisomerase II - drug interaction domains: identification of substituents on etoposide that interact with the enzyme.

AFFILIATION: Departments of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.

Country: United States

AGENCY: United States NCI

GRANT: T32 CA09582

ACRONYM: CA

MEDLINETA: Biochemistry

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