Abstract:
:Kinetics studies of dNTP analogues having pyrophosphate-mimicking β,γ-pCXYp leaving groups with variable X and Y substitution reveal striking differences in the chemical transition-state energy for DNA polymerase β that depend on all aspects of base-pairing configurations, including whether the incoming dNTP is a purine or pyrimidine and if base-pairings are right (T•A and G•C) or wrong (T•G and G•T). Brønsted plots of the catalytic rate constant (log(kpol)) versus pKa4 for the leaving group exhibit linear free energy relationships (LFERs) with negative slopes ranging from -0.6 to -2.0, consistent with chemical rate-determining transition-states in which the active-site adjusts to charge-stabilization demand during chemistry depending on base-pair configuration. The Brønsted slopes as well as the intercepts differ dramatically and provide the first direct evidence that dNTP base recognition by the enzyme-primer-template complex triggers a conformational change in the catalytic region of the active-site that significantly modifies the rate-determining chemical step.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Oertell K,Chamberlain BT,Wu Y,Ferri E,Kashemirov BA,Beard WA,Wilson SH,McKenna CE,Goodman MFdoi
10.1021/bi500101zsubject
Has Abstractpub_date
2014-03-25 00:00:00pages
1842-8issue
11eissn
0006-2960issn
1520-4995journal_volume
53pub_type
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