Structural basis for inhibition of DNA replication by aphidicolin

Baranovskiy, A. G.; Babayeva, N. D.; Suwa, Y.; Gu, J.; Pavlov, Y. I.; Tahirov, T. H.

doi:10.1093/nar/gku1209

Title: Structural basis for inhibition of DNA replication by aphidicolin

Journal Article · Thu Nov 27 00:00:00 EST 2014 · Nucleic Acids Research

DOI:https://doi.org/10.1093/nar/gku1209· OSTI ID:1168507

Baranovskiy, A. G. ^[1]; Babayeva, N. D. ^[1]; Suwa, Y. ^[1]; Gu, J. ^[1]; Pavlov, Y. I. ^[2]; Tahirov, T. H. ^[1]

Univ. of Nebraska Medical Center, Omaha, NE (United States). Eppley Inst. for Research in Cancer and Allied Diseases
Univ. of Nebraska Medical Center, Omaha, NE (United States). Eppley Inst. for Research in Cancer and Allied Diseases, Dept. of Biochemistry and Molecular Biology and Dept. of Pathology and Microbiology

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 α (Pol α) in the ternary complex with an RNA-primed DNA template and aphidicolin. The inhibitor blocks binding of dCTP by docking at the Pol α 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 α. 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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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC); National Institute of General Medical Sciences; National Cancer Institute (NCI)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1168507

Journal Information:: Nucleic Acids Research, Vol. 42, Issue 22; ISSN 0305-1048

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 82 works

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