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Nucleic Acids Research, 1992, Vol. 20, No. 14 3561-3566
© 1992

STRUCTURAL BIOLOGY

The molecular structure of a 4'–epiadrimamycin complex with d(TGATCA) at 1.7Å resolution: comparison with the structure of 4'–epiadriamycin d(TGTACA) and d(CGATCG) complexes

Beatrice Langlois d'Estaintot1, Bernard Gallois1,2, Tom Brown3 and William N. Hunter2,*

1Laboratoire de Cristallographie, URA CNRS 144, Université de Bordeaux 1, 351 Cours de la Libération, 33405 Talence Cedex, France 2Department of Chemistry, University of Manchester Oxford Road, Manchester M13 9PL 3Department of Chemistry, University of Edinburgh West Mains Road, Edinburgh, UK

To whom correspondence should be addressed

Received May 27, 1992. Accepted June 26, 1992.

The structure of the complex between d(TGATCA) and the anthracycllne 4'-epladriamycln has been determined by crystallographlc methods. The crystals are tetragonal, space group P41212 with unit cell dimensions of a= 28.01, c=52.95Å. The asymmetric unit consists of one strand of hexanucleotide, one molecule of 4'-epiadriamycin and 34 waters. The R-factor is 20.2% for 1694 reflections with F ≤:2o F to 1.7Å. Two asymmetric units associate to generate a duplex complexed with two drug molecules at the d(TpG) steps of the duplex. The chromophore intercalates between these base pairs with the anthracycline amino-sugar positioned in the minor groove. The double helix is a distorted B-DNA type structure. Our structure determination of d(TGATCA) complexed to 4'-epiadriamydn allows for comparison with the previously reported structures of 4'-epiadriamycin bound to d(TGTACA) and to d(CGATCG). The three complexes are similar in gross features and the intercalation geometry is the same Irrespective of whether a d(CpG) or d(TpG) sequence Is involved. However, the orientation of the amino-sugar displays a dependence on the sequence adjacent to the intercalation site. The flexibility of this amino-sugar may help explain why this class of antibiotics displays a relative insensitivity to base sequence when they bind to DNA.


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