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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1995 Nov 7;92(23):10506–10510. doi: 10.1073/pnas.92.23.10506

Calicheamicin-DNA complexes: warhead alignment and saccharide recognition of the minor groove.

N Ikemoto 1, R A Kumar 1, T T Ling 1, G A Ellestad 1, S J Danishefsky 1, D J Patel 1
PMCID: PMC40640  PMID: 7479829

Abstract

The solution structures of calicheamicin gamma 1I, its cycloaromatized analog (calicheamicin epsilon), and its aryl tetrasaccharide complexed to a common DNA hairpin duplex have been determined by NMR and distance-refined molecular dynamics computations. Sequence specificity is associated with carbohydrate-DNA recognition that places the aryl tetrasaccharide component of all three ligands in similar orientations in the minor groove at the d(T-C-C-T).d(A-G-G-A) segment. The complementary fit of the ligands and the DNA minor groove binding site creates numerous van der Waals contacts as well as hydrogen bonding interactions. Notable are the iodine and sulfur atoms of calicheamicin that hydrogen bond with the exposed amino proton of the 5'- and 3'-guanines, respectively, of the d(A-G-G-A) segment. The sequence-specific carbohydrate binding orients the enediyne aglycone of calicheamicin gamma 1I such that its C3 and C6 proradical centers are adjacent to the cleavage sites. While the enediyne aglycone of calicheamicin gamma 1I is tilted relative to the helix axis and spans the minor groove, the cycloaromatized aglycone is aligned approximately parallel to the helix axis in the respective complexes. Specific localized conformational perturbations in the DNA have been identified from imino proton complexation shifts and changes in specific sugar pucker patterns on complex formation. The helical parameters for the carbohydrate binding site are comparable with corresponding values in B-DNA fibers while a widening of the groove is observed at the adjacent aglycone binding site.

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Selected References

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  1. Dedon P. C., Salzberg A. A., Xu J. Exclusive production of bistranded DNA damage by calicheamicin. Biochemistry. 1993 Apr 13;32(14):3617–3622. doi: 10.1021/bi00065a013. [DOI] [PubMed] [Google Scholar]
  2. Drak J., Iwasawa N., Danishefsky S., Crothers D. M. The carbohydrate domain of calicheamicin gamma I1 determines its sequence specificity for DNA cleavage. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7464–7468. doi: 10.1073/pnas.88.17.7464. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Hawley R. C., Kiessling L. L., Schreiber S. L. Model of the interactions of calichemicin gamma 1 with a DNA fragment from pBR322. Proc Natl Acad Sci U S A. 1989 Feb;86(4):1105–1109. doi: 10.1073/pnas.86.4.1105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Ho S. N., Boyer S. H., Schreiber S. L., Danishefsky S. J., Crabtree G. R. Specific inhibition of formation of transcription complexes by a calicheamicin oligosaccharide: a paradigm for the development of transcriptional antagonists. Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9203–9207. doi: 10.1073/pnas.91.20.9203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Mah S. C., Townsend C. A., Tullius T. D. Hydroxyl radical footprinting of calicheamicin. Relationship of DNA binding to cleavage. Biochemistry. 1994 Jan 18;33(2):614–621. doi: 10.1021/bi00168a029. [DOI] [PubMed] [Google Scholar]
  6. Piotto M., Saudek V., Sklenár V. Gradient-tailored excitation for single-quantum NMR spectroscopy of aqueous solutions. J Biomol NMR. 1992 Nov;2(6):661–665. doi: 10.1007/BF02192855. [DOI] [PubMed] [Google Scholar]
  7. Walker S., Landovitz R., Ding W. D., Ellestad G. A., Kahne D. Cleavage behavior of calicheamicin gamma 1 and calicheamicin T. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4608–4612. doi: 10.1073/pnas.89.10.4608. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Zein N., Poncin M., Nilakantan R., Ellestad G. A. Calicheamicin gamma 1I and DNA: molecular recognition process responsible for site-specificity. Science. 1989 May 12;244(4905):697–699. doi: 10.1126/science.2717946. [DOI] [PubMed] [Google Scholar]
  9. Zein N., Sinha A. M., McGahren W. J., Ellestad G. A. Calicheamicin gamma 1I: an antitumor antibiotic that cleaves double-stranded DNA site specifically. Science. 1988 May 27;240(4856):1198–1201. doi: 10.1126/science.3240341. [DOI] [PubMed] [Google Scholar]

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