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Human topoisomerase I inhibition: docking camptothecin and derivatives into a structure-based active site model.
Biochemistry. 2002 Feb 05; 41(5):1428-35.B

Abstract

Human topoisomerase I (top1) is an important target for anti-cancer drugs, which include camptothecin (CPT) and its derivatives. To elucidate top1 inhibition in vitro, we made a series of duplex DNA substrates containing a deoxyadenosine stereospecifically modified by a covalent adduct of benzo[a]pyrene (BaP) diol epoxide [Pommier, Y., et al. (2000) Proc. Natl. Acad. Sci. U.S.A. 97, 10739-10744]. The known orientation of the hydrocarbon adduct in the DNA duplex relative to the top1 cleavage site, in combination with a top1/DNA crystal structure [Redinbo, M. R., et al. (1998) Science 279, 1504-1513], was used to construct a structure-based model to explain the in vitro top1 inhibition results obtained with adducted DNA duplexes. Here we experimentally determined that the lactone form of CPT was stabilized by an irreversible top1/DNA covalent complex. We removed the BaP moiety from the DNA in the published model, and docked the lactone forms of CPT and derivatives into the top1/DNA active site cavity. The docked ligands were minimized, and interaction energy scores between the ligands and the top1/DNA complex were determined. CPT docks perpendicular to the DNA backbone, projects outward from the major groove, and makes a network of potential H-bonds with the active site DNA and top1 residues, including Arg364, Lys532, and Asn722. The results are consistent with the known structure-activity relationships of CPT and derivatives. In addition, the model proposed a novel top1/N352A "resistance" mutation for 10-OH derivatives of CPT. The in vitro biochemical characterization of the top1/N352A mutant supported the model.

Authors+Show Affiliations

Laboratory of Molecular Pharmacology, Division of Basic Sciences, National Cancer Institute, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11814334

Citation

Laco, Gary S., et al. "Human Topoisomerase I Inhibition: Docking Camptothecin and Derivatives Into a Structure-based Active Site Model." Biochemistry, vol. 41, no. 5, 2002, pp. 1428-35.
Laco GS, Collins JR, Luke BT, et al. Human topoisomerase I inhibition: docking camptothecin and derivatives into a structure-based active site model. Biochemistry. 2002;41(5):1428-35.
Laco, G. S., Collins, J. R., Luke, B. T., Kroth, H., Sayer, J. M., Jerina, D. M., & Pommier, Y. (2002). Human topoisomerase I inhibition: docking camptothecin and derivatives into a structure-based active site model. Biochemistry, 41(5), 1428-35.
Laco GS, et al. Human Topoisomerase I Inhibition: Docking Camptothecin and Derivatives Into a Structure-based Active Site Model. Biochemistry. 2002 Feb 5;41(5):1428-35. PubMed PMID: 11814334.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Human topoisomerase I inhibition: docking camptothecin and derivatives into a structure-based active site model. AU - Laco,Gary S, AU - Collins,Jack R, AU - Luke,Brian T, AU - Kroth,Heiko, AU - Sayer,Jane M, AU - Jerina,Donald M, AU - Pommier,Yves, PY - 2002/1/30/pubmed PY - 2002/2/20/medline PY - 2002/1/30/entrez SP - 1428 EP - 35 JF - Biochemistry JO - Biochemistry VL - 41 IS - 5 N2 - Human topoisomerase I (top1) is an important target for anti-cancer drugs, which include camptothecin (CPT) and its derivatives. To elucidate top1 inhibition in vitro, we made a series of duplex DNA substrates containing a deoxyadenosine stereospecifically modified by a covalent adduct of benzo[a]pyrene (BaP) diol epoxide [Pommier, Y., et al. (2000) Proc. Natl. Acad. Sci. U.S.A. 97, 10739-10744]. The known orientation of the hydrocarbon adduct in the DNA duplex relative to the top1 cleavage site, in combination with a top1/DNA crystal structure [Redinbo, M. R., et al. (1998) Science 279, 1504-1513], was used to construct a structure-based model to explain the in vitro top1 inhibition results obtained with adducted DNA duplexes. Here we experimentally determined that the lactone form of CPT was stabilized by an irreversible top1/DNA covalent complex. We removed the BaP moiety from the DNA in the published model, and docked the lactone forms of CPT and derivatives into the top1/DNA active site cavity. The docked ligands were minimized, and interaction energy scores between the ligands and the top1/DNA complex were determined. CPT docks perpendicular to the DNA backbone, projects outward from the major groove, and makes a network of potential H-bonds with the active site DNA and top1 residues, including Arg364, Lys532, and Asn722. The results are consistent with the known structure-activity relationships of CPT and derivatives. In addition, the model proposed a novel top1/N352A "resistance" mutation for 10-OH derivatives of CPT. The in vitro biochemical characterization of the top1/N352A mutant supported the model. SN - 0006-2960 UR - https://www.unboundmedicine.com/medline/citation/11814334/Human_topoisomerase_I_inhibition:_docking_camptothecin_and_derivatives_into_a_structure_based_active_site_model_ L2 - https://doi.org/10.1021/bi011774a DB - PRIME DP - Unbound Medicine ER -