Publication Date:
1998-03-21
Description:
Topoisomerases I promote the relaxation of DNA superhelical tension by introducing a transient single-stranded break in duplex DNA and are vital for the processes of replication, transcription, and recombination. The crystal structures at 2.1 and 2.5 angstrom resolution of reconstituted human topoisomerase I comprising the core and carboxyl-terminal domains in covalent and noncovalent complexes with 22-base pair DNA duplexes reveal an enzyme that "clamps" around essentially B-form DNA. The core domain and the first eight residues of the carboxyl-terminal domain of the enzyme, including the active-site nucleophile tyrosine-723, share significant structural similarity with the bacteriophage family of DNA integrases. A binding mode for the anticancer drug camptothecin is proposed on the basis of chemical and biochemical information combined with these three-dimensional structures of topoisomerase I-DNA complexes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Redinbo, M R -- Stewart, L -- Kuhn, P -- Champoux, J J -- Hol, W G -- CA65656/CA/NCI NIH HHS/ -- GM49156/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 1998 Mar 6;279(5356):1504-13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Biomolecular Structure Center and Department of Biological Structure, Box 357742, School of Medicine, University of Washington, Seattle, WA 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9488644" target="_blank"〉PubMed〈/a〉
Keywords:
Antineoplastic Agents, Phytogenic/metabolism/pharmacology
;
Binding Sites
;
Camptothecin/analogs & derivatives/metabolism/pharmacology
;
Crystallography, X-Ray
;
DNA/chemistry/*metabolism
;
DNA Topoisomerases, Type I/*chemistry/genetics/metabolism
;
*DNA-Binding Proteins
;
Homeodomain Proteins/chemistry
;
Host Cell Factor C1
;
Humans
;
Hydrogen Bonding
;
Integrases/chemistry
;
Models, Molecular
;
Mutation
;
Nucleic Acid Conformation
;
Octamer Transcription Factor-1
;
Oligodeoxyribonucleotides/chemistry/metabolism
;
*Protein Conformation
;
Protein Structure, Secondary
;
Recombinant Proteins/chemistry
;
Transcription Factors/chemistry
;
Tyrosine/chemistry/metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
