STRUCTURAL CHARACTERIZATION OF A CALICHEAMICIN DNA COMPLEX BY NMR

The enediynes, including neocarzinostatin, calicheamicin, esperamicin, and dyneamicin, are an important class of antitumor antibiotics that cleave DNA. In spite of intense interest in the enediynes as potential drugs, there is no detailed structural information about how any of these compounds interacts with DNA. We report the first NMR studies of a complex between an enediyne, calicheamicin gamma1, and DNA. Calicheamicin gamma1 cleaves DNA in a double-stranded fashion at oligopyrimidine/oligopurine sequences. The molecular basis for the selective recognition of pyrimidine/purine runs is not well understood. Using NMR we have shown that calicheamicin gamma1 binds to the non-self-complementary DNA duplex, d[GTGACCTG]-d[CAGGTCAC], where ACCT is the recognition sequence. The DNA distorts upon binding to accommodate the drug. The distortion is largest at the CpC step of the recognition sequence and appears to be associated with a widening of the minor groove. A preliminary analysis of the data indicates that the drug itself does not distort much upon binding. It is proposed that binding selectivity reflects the ability of oligopyrimidine sequences to distort to accommodate the more rigid drug.