Case DA,Eis PS, Smith JA, Rydzewski JM, , Boger DL, Chazin WJ
Department of Molecular Biology
The Scripps Research Institute


Eis PS, Smith JA, Rydzewski JM, Case DA, Boger DL, Chazin WJ
Journal of Molecular Biology 1997,272: 237-252
High resolution solution structure of a DNA duplex alkylated by the antitumor agent duocarmycin SA
The three-dimensional solution structure of duocarmycin SA in complex with d-(G(1)ACTAATTGAC(11)).d-(G(12)TCATT (A) under bar GTC(22)) has been determined by restrained molecular dynamics and relaxation matrix calculations using experimental NOE distance and torsion angle constraints derived from H-1 NMR spectroscopy. The final input data consisted of a total of 858 distance and 189 dihedral angle constraints, an average of 46 constraints per residue. Ln the ensemble of 20 final structures, there were no distance constraint violations >0.06 Angstrom or torsion angle violations >0.8 degrees. The average pairwise root mean square deviation (RMSD) over all 20 structures for the binding site region is 0.57 Angstrom (average RMSD from the mean: 0.39 Angstrom). Although the DNA is very B-Like, the sugar-phosphate backbone torsion angles beta, epsilon, and zeta are distorted from standard values in the binding site region. The structure reveals site-specific bonding of duocarmycin SA at the N3 position of adenine 19 in the AT-rich minor groove of the duplex and binding stabilization via hydrophobic interactions. Comparisons have been made to the structure of a closely related complex of duocarmycin A bound to an AT-rich DNA duplex. These results provide insights into critical aspects of the alkylation site selectivity and source of catalysis of the DNA alkylating agents, and the unusual stability of the resulting adducts. (C) 1997 Academic Press Limited.


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