A structural model for the ternary cleavable complex formed between human topoisomerase I, DNA, and camptothecin.
Using the X-ray crystal structure of the human topoisomerase I (TOP1)-DNA cleavable complex, we have developed a general model for the ternary drug-DNA-TOP1 cleavable complex formed with camptothecin (CPT) and its analogues. This model has the drug intercalated between the -1 and +1 base pairs, with the E-ring pointing into the minor groove and the A-ring directed toward the major groove. The ternary complex is stabilized by an array of hydrogen bonding and hydrophobic interactions between the drug and both the enzyme and the DNA. Significantly, the proposed model is consistent with the current body of experimental mutation, cross-linking, and structure-activity data. In addition, the model reveals potential sites of interaction that can provide a rational basis for the design of next generation compounds as well as for de novo drug design.
Kerrigan
J E
JE
Department of Pharmaceutical Chemistry, College of Pharmacy, Rutgers-The State University of New Jersey, Piscataway, New Jersey 08854-8087, USA. jkerriga@cop.rutgers.edu
Pilch
D S
DS
D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology; D001483:Base Sequence; D002166:Camptothecin / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004247:DNA / Q000737:chemistry* / Q000378:metabolism*; D004264:DNA Topoisomerases, Type I / Q000737:chemistry* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding
D000972:Antineoplastic Agents, Phytogenic; D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D004247:DNA; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin