4Q5V

Crystal structure of the catalytic core of human DNA polymerase alpha in ternary complex with an RNA-primed DNA template and aphidicolin

Summary for 4Q5V

• Entry DOI: 10.2210/pdb4q5v/pdb
• Descriptor: DNA polymerase alpha catalytic subunit, RNA primer, DNA template, ... (5 entities in total)
• Functional Keywords: b-family dna polymerase, dna replication, transferase-dna-rna complex, transferase/dna/rna
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P09884
• Total number of polymer chains: 6
• Total formula weight: 231733.23

Authors

Baranovskiy, A.G.,Babayeva, N.D.,Suwa, Y.,Gu, J.,Tahirov, T.H. (deposition date: 2014-04-17, release date: 2014-11-26, Last modification date: 2024-02-28)

Primary citation

Baranovskiy, A.G.,Babayeva, N.D.,Suwa, Y.,Gu, J.,Pavlov, Y.I.,Tahirov, T.H.
Structural basis for inhibition of DNA replication by aphidicolin.
Nucleic Acids Res., 42:14013-14021, 2014

PubMed 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 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.

PubMed: 25429975
DOI: 10.1093/nar/gku1209

Experimental method

X-RAY DIFFRACTION (2.52 Å)