385d
From Proteopedia
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FORMATION OF A NEW COMPOUND IN THE CRYSTAL STRUCTURE OF CYANOMORPHOLINODOXORUBICIN COMPLEXED WITH D(CGATCG)
Overview
The cyanomorpholino analogue of antitumor anthracycline doxorubicin, possesses an intense potency and differs from the parent compound in, cross-resistance and other biological properties. The induction by, cyanomorpholinodoxorubicin of both DNA cross-links and strand scission, suggests an altered mode of action relative to doxorubicin with a, different DNA-interacting capacity. We have co-crystallized, 3'-(3-cyano-4-morpholinyl)-3'-desaminodoxorubicin (CMD) with the DNA, hexamer d(CGATCG) and have determined the crystal structure at 0.16-nm, resolution. The complex crystallizes in the space group P4(1)2(1)2 and is, similar to the previously reported anthracycline/DNA structures, with the, drug intercalated at the CpG step, forming hydrogen bonds with the guanine, residue. The structure reveals that the morpholino moiety has undergone a, major rearrangement with loss of the cyano group and opening of the, morpholino ring. The compound actually bound to DNA in the complex, resembles N-(2-hydroxyethyl)doxorubicin, which was previously identified, as a hydrolysis product of CMD. No DNA alkylation has been observed., However, the structure shows that the active site of the morpholino ring, after dissociation of the cyano group, lies in the minor groove in, proximity of the A/T base pair. This may indicate that a C/G base pair, next to the intercalation site, with NH2 group in the minor groove, is, required for DNA alkylation.
About this Structure
385D is a Protein complex structure of sequences from [1] with as ligand. Full crystallographic information is available from OCA.
Reference
Degradation of the morpholino ring in the crystal structure of cyanomorpholinodoxorubicin complexed with d(CGATCG)., Ettorre A, Cirilli M, Ughetto G, Eur J Biochem. 1998 Dec 1;258(2):350-4. PMID:9874199
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