Evaluating the Substrate Selectivity of Alkyladenine DNA Glycosylase: The Synergistic Interplay of Active Site Flexibility and Water Reorganization

Biochemistry
Stefan A P Lenz, Stacey D Wetmore

Abstract

Human alkyladenine DNA glycosylase (AAG) functions as part of the base excision repair (BER) pathway by cleaving the N-glycosidic bond that connects nucleobases to the sugar-phosphate backbone in DNA. AAG targets a range of structurally diverse purine lesions using nonspecific DNA-protein π-π interactions. Nevertheless, the enzyme discriminates against the natural purines and is inhibited by pyrimidine lesions. This study uses molecular dynamics simulations and seven different neutral or charged substrates, inhibitors, or canonical purines to probe how the bound nucleotide affects the conformation of the AAG active site, and the role of active site residues in dictating substrate selectivity. The neutral substrates form a common DNA-protein hydrogen bond, which results in a consistent active site conformation that maximizes π-π interactions between the aromatic residues and the nucleobase required for catalysis. Nevertheless, subtle differences in DNA-enzyme contacts for different neutral substrates explain observed differential catalytic efficiencies. In contrast, the exocyclic amino groups of the natural purines clash with active site residues, which leads to catalytically incompetent DNA-enzyme complexes due to significant r...Continue Reading

References

Dec 20, 1985·Nucleic Acids Research·F H MartinI Tinoco
May 11, 2000·Proceedings of the National Academy of Sciences of the United States of America·S S ParikhJ A Tainer
Dec 6, 2000·Proceedings of the National Academy of Sciences of the United States of America·A Y LauT Ellenberger
Jul 18, 2001·Journal of the American Chemical Society·D P NormanG L Verdine
Jul 10, 2003·Chemical Reviews·James T Stivers, Yu Lin Jiang
Dec 23, 2003·The Journal of Biological Chemistry·Patrick J O'Brien, Tom Ellenberger
Feb 6, 2004·The Journal of Biological Chemistry·Laurent GrosMurat K Saparbaev
Mar 3, 2004·Archives of Biochemistry and Biophysics·Peter C Dedon, Steven R Tannenbaum
Mar 26, 2004·Nature Reviews. Molecular Cell Biology·Barbara Sedgwick
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
Dec 15, 2006·Journal of the American Chemical Society·Demian RiccardiQiang Cui
Dec 12, 2007·Journal of Computational Chemistry·Ross C WalkerDavid A Case
Feb 9, 2008·Cellular and Molecular Life Sciences : CMLS·D O Zharkov
May 26, 2009·Mutation Research·Gunnar BoysenJames A Swenberg
Oct 21, 2009·Proceedings of the National Academy of Sciences of the United States of America·Seongmin Lee, Gregory L Verdine
Oct 31, 2009·Mutation Research·Paola MontiGilberto Fronza
Nov 27, 2009·Accounts of Chemical Research·Sriram KanvahUzi Landman
Jun 25, 2010·Physical Chemistry Chemical Physics : PCCP·François-Yves DupradeauPiotr Cieplak
Feb 26, 2011·The Journal of Biological Chemistry·Gondichatnahalli M LingarajuCatherine L Drennan
Apr 9, 2011·Biochemistry·Jennifer L Przybylski, Stacey D Wetmore
Apr 9, 2011·Journal of the American Chemical Society·Jason D Perlmutter, Jonathan N Sachs
May 17, 2011·Biochemistry. Biokhimii︠a︡·N A KuznetsovO S Fedorova
Jan 20, 2012·Free Radical Research·Alicja WinczuraBarbara Tudek
Mar 28, 2012·Nucleic Acids Research·Kamila RéblováFilip Lankas
Apr 28, 2012·Journal of the American Chemical Society·Elizabeth BrunkUrsula Rothlisberger
Jun 30, 2012·The Journal of Physical Chemistry. B·WenJuan HuangJames W Gauld
Oct 19, 2012·Biochimica Et Biophysica Acta·Sonja C BrooksBrandt F Eichman

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Citations

Aug 14, 2020·Proceedings of the National Academy of Sciences of the United States of America·Yaojuan LiuVivian G Cheung
Apr 9, 2020·Langmuir : the ACS Journal of Surfaces and Colloids·Sandip Mondal, Sanjoy Bandyopadhyay
May 22, 2021·Journal of Chemical Theory and Computation·Cui LiuZhong-Zhi Yang
Jul 1, 2021·Computational and Structural Biotechnology Journal·Nicole M HoitsmaBret D Freudenthal

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