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Mapping Functional Substrate-Enzyme Interactions in the pol β Active Site through Chemical Biology: Structural Responses to Acidity Modification of Incoming dNTPs.

Batra VK, Oertell K, Beard WA, Kashemirov BA, McKenna CE, Goodman MF, Wilson SH
Biochemistry 57 3934-3944 (2018)

Cited: 5 times
EuropePMC logo PMID: 29874056

Abstract

We report high-resolution crystal structures of DNA polymerase (pol) β in ternary complex with a panel of incoming dNTPs carrying acidity-modified 5'-triphosphate groups. These novel dNTP analogues have a variety of halomethylene substitutions replacing the bridging oxygen between Pβ and Pγ of the incoming dNTP, whereas other analogues have alkaline substitutions at the bridging oxygen. Use of these analogues allows the first systematic comparison of effects of 5'-triphosphate acidity modification on active site structures and the rate constant of DNA synthesis. These ternary complex structures with incoming dATP, dTTP, and dCTP analogues reveal the enzyme's active site is not grossly altered by the acidity modifications of the triphosphate group, yet with analogues of all three incoming dNTP bases, subtle structural differences are apparent in interactions around the nascent base pair and at the guanidinium groups of active site arginine residues. These results are important for understanding how acidity modification of the incoming dNTP's 5'-triphosphate can influence DNA polymerase activity and the significance of interactions at arginines 183 and 149 in the active site.

Articles citing this publication (5)

  1. A Transition-State Perspective on Y-Family DNA Polymerase η Fidelity in Comparison with X-Family DNA Polymerases λ and β. Oertell K, Florián J, Haratipour P, Crans DC, Kashemirov BA, Wilson SH, McKenna CE, Goodman MF. Biochemistry 58 1764-1773 (2019)
  2. New Chirally Modified Bisphosphonates for Synthesis of Individual Beta,Gamma-CHX-Deoxynucleotide Diastereomers. Haratipour P, Minard C, Nakhjiri M, Negahbani A, Kashemirov BA, McKenna CE. Phosphorus Sulfur Silicon Relat Elem 194 329-330 (2019)
  3. Preferential DNA Polymerase β Reverse Reaction with Imidodiphosphate. Perera L, Beard WA, Pedersen LG, Shock DD, Wilson SH. ACS Omega 5 15317-15324 (2020)
  4. Revealing an Internal Stabilization Deficiency in the DNA Polymerase β K289M Cancer Variant through the Combined Use of Chemical Biology and X-ray Crystallography. Batra VK, Alnajjar KS, Sweasy JB, McKenna CE, Goodman MF, Wilson SH. Biochemistry 59 955-963 (2020)
  5. Synthesis of 8-oxo-dGTP and its β,γ-CH2-, β, γ-CHF-, and β, γ-CF2- analogues. Zheng Y, Haratipour P, Kashemirov BA, McKenna CE. Tetrahedron Lett 67 152890 (2021)


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