235d
From Proteopedia
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CRYSTAL STRUCTURE OF FOUR MORPHOLINO-DOXORUBICIN ANTICANCER DRUGS COMPLEXED WITH D(CGTACG) AND D(CGATCG): IMPLICATIONS IN DRUG-DNA CROSSLINK
Overview
Among the new generations of anthracycline drugs, morpholino-doxorubicin, (MDox) and its derivative have unusually potent activity when compared, with the parent doxorubicin. 3"-Cyano-morpholino-doxorubicin (CN-MDox) has, been suggested to form a covalent crosslink to DNA, although the exact, mode of interactions remains unclear. To establish the structural basis of, this crosslink, we carried out X-ray diffraction analyses of the complexes, between four different morpholino-doxorubicins (i.e., MDox, CN-MDox, (R)-, and (S)-2"-methoxy-morpholino-Dox (MMDox)) and two DNA hexamers CGTACG and, CGATCG. Their crystal data are similar to other Dau/Dox complexes with, space group P4(1)2(1)2,a = b approximately 28 A, c approximately 53 A. The, refined structures at approximately 1.8 A resolution revealed that two, drug molecules bind to the duplex with the aglycons intercalated between, the CpG steps with their N3'-morpholino-daunosamines in the minor groove., The morpholino moiety is flexible and may adopt different conformations, dependent on the sequence context. The O1" atoms of the two morpholino, groups in the drug-DNA complexes are in van der Waals contact. The, structural results suggest possible crosslinking mechanism of CN-MDox. It, is worth pointing out that by linking two piperazinyl- or, piperidinyl-doxorubicins at the 1" positions a new type of bis-doxorubicin, derivatives may be synthesized which may bind to a hexanucleotide sequence, with some specificity.
About this Structure
235D is a Protein complex structure of sequences from [1] with as ligand. Full crystallographic information is available from OCA.
Reference
Crystal structures of four morpholino-doxorubicin anticancer drugs complexed with d(CGTACG) and d(CGATCG): implications in drug-DNA crosslink., Gao YG, Wang AH, J Biomol Struct Dyn. 1995 Aug;13(1):103-17. PMID:8527023
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