Structural basis for inhibition of DNA replication by aphidicolin.

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Baranovskiy AG, Babayeva ND, Suwa Y, Gu J, Pavlov YI, Tahirov TH

Structural basis for inhibition of DNA replication by aphidicolin.

Nucleic Acids Res. 2014 Dec 16;42(22):14013-21. doi: 10.1093/nar/gku1209. Epub 2014 Nov 27.

PubMed ID
25429975 [ View in PubMed
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Abstract

Natural tetracyclic diterpenoid aphidicolin is a potent and specific inhibitor of B-family DNA polymerases, haltering replication and possessing a strong antimitotic activity in human cancer cell lines. Clinical trials revealed limitations of aphidicolin as an antitumor drug because of its low solubility and fast clearance from human plasma. The absence of structural information hampered the improvement of aphidicolin-like inhibitors: more than 50 modifications have been generated so far, but all have lost the inhibitory and antitumor properties. Here we report the crystal structure of the catalytic core of human DNA polymerase alpha (Pol alpha) in the ternary complex with an RNA-primed DNA template and aphidicolin. The inhibitor blocks binding of dCTP by docking at the Pol alpha active site and by rotating the template guanine. The structure provides a plausible mechanism for the selectivity of aphidicolin incorporation opposite template guanine and explains why previous modifications of aphidicolin failed to improve its affinity for Pol alpha. With new structural information, aphidicolin becomes an attractive lead compound for the design of novel derivatives with enhanced inhibitory properties for B-family DNA polymerases.

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