To examine the hypothesis that interactions between a DNA polymerase and the DNA minor groove are critical for accurate DNA synthesis, we studied the fidelity of DNA polymerase beta mutants at residue Arg(283), where arginine, which interacts with the minor groove at the active site, is replaced by alanine or lysine. Alanine substitution, removing minor groove interactions, strongly reduces polymerase selectivity for all single-base mispairs examined. In contrast, the lysine substitution, which retains significant interactions with the minor groove, has wild-type-like selectivity for T.dGMP and A.dGMP mispairs but reduced selectivity for T.dCMP and A.dCMP mispairs, Examination of DNA crystal structures of these four mispairs indicates that the two mispairs excluded by the lysine mutant have an atom (N2) in an unfavorable position in the minor groove, while the two mispairs permitted by the lysine mutant do not. These results suggest that unfavorable interactions between an active site amino acid side chain and mispair-specific atoms in the minor groove contribute to DNA polymerase specificity.
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Univ Sains Malaysia, Sch Pharmaceut Sci, Dept Pharmacol, George Town 11800, MalaysiaUniv Sains Malaysia, Sch Pharmaceut Sci, Dept Pharmacol, George Town 11800, Malaysia
Helal, Muath H.
Al-Mudaris, Zena A.
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Univ Sains Malaysia, Sch Pharmaceut Sci, Dept Pharmacol, George Town 11800, MalaysiaUniv Sains Malaysia, Sch Pharmaceut Sci, Dept Pharmacol, George Town 11800, Malaysia
Al-Mudaris, Zena A.
Al-Douh, Mohammed H.
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Univ Sains Malaysia, Sch Chem Sci, George Town 11800, MalaysiaUniv Sains Malaysia, Sch Pharmaceut Sci, Dept Pharmacol, George Town 11800, Malaysia
Al-Douh, Mohammed H.
Osman, Hasnah
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Univ Sains Malaysia, Sch Chem Sci, George Town 11800, MalaysiaUniv Sains Malaysia, Sch Pharmaceut Sci, Dept Pharmacol, George Town 11800, Malaysia
Osman, Hasnah
Wahab, Habibah A.
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Univ Sains Malaysia, Sch Pharmaceut Sci, Dept Pharmacol, George Town 11800, MalaysiaUniv Sains Malaysia, Sch Pharmaceut Sci, Dept Pharmacol, George Town 11800, Malaysia
Wahab, Habibah A.
Alnajjar, Belal O.
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Univ Sains Malaysia, Sch Pharmaceut Sci, Dept Pharmacol, George Town 11800, MalaysiaUniv Sains Malaysia, Sch Pharmaceut Sci, Dept Pharmacol, George Town 11800, Malaysia
Alnajjar, Belal O.
Abdallah, Hassan H.
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Univ Sains Malaysia, Sch Chem Sci, George Town 11800, MalaysiaUniv Sains Malaysia, Sch Pharmaceut Sci, Dept Pharmacol, George Town 11800, Malaysia
Abdallah, Hassan H.
Majid, Amin M. S. Abdul
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Univ Sains Malaysia, Sch Pharmaceut Sci, Dept Pharmacol, George Town 11800, MalaysiaUniv Sains Malaysia, Sch Pharmaceut Sci, Dept Pharmacol, George Town 11800, Malaysia
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Museum Natl Hist Nat, Biophys Lab, CNRS, URA 481,INSERM,U201, F-75231 Paris 05, FranceMuseum Natl Hist Nat, Biophys Lab, CNRS, URA 481,INSERM,U201, F-75231 Paris 05, France