1DSA

(+)-DUOCARMYCIN SA COVALENTLY LINKED TO DUPLEX DNA, NMR, 20 STRUCTURES

Summary for 1DSA

• Entry DOI: 10.2210/pdb1dsa/pdb
• Descriptor: DNA (5'-D(*GP*AP*CP*TP*AP*AP*TP*TP*GP*AP*C)-3', 5'-D(*GP*TP*CP*AP*AP*TP*TP*AP*GP*TP*C)-3'), 4-HYDROXY-8-METHYL-6-(4,5,6-TRIMETHOXY-1H-INDOLE-2-CARBONYL)-3,6,7,8-TETRAHYDRO-3,6-DIAZA-AS-INDACENE-2-CARBOXYLIC ACID METHYL ESTER (3 entities in total)
• Functional Keywords: duocarmycin, dna, minor groove binding, antitumor agent, drug-dna complex, deoxyribonucleic acid
• Total number of polymer chains: 2
• Total formula weight: 7184.91

Authors

Eis, P.S.,Smith, J.A.,Case, D.A.,Chazin, W.J. (deposition date: 1997-05-08, release date: 1997-08-20, Last modification date: 2024-05-22)

Primary citation

Eis, P.S.,Smith, J.A.,Rydzewski, J.M.,Case, D.A.,Boger, D.L.,Chazin, W.J.
High resolution solution structure of a DNA duplex alkylated by the antitumor agent duocarmycin SA.
J.Mol.Biol., 272:237-252, 1997

PubMed Abstract: The three-dimensional solution structure of duocarmycin SA in complex with d-(G1ACTAATTGAC11).d-(G12TCATTAGTC22) has been determined by restrained molecular dynamics and relaxation matrix calculations using experimental NOE distance and torsion angle constraints derived from 1H 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. In the ensemble of 20 final structures, there were no distance constraint violations >0.06 A 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 A (average RMSD from the mean: 0.39 A). 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.

PubMed: 9299351
DOI: 10.1006/jmbi.1997.1223

Experimental method

SOLUTION NMR