DNA binding and nucleotide flipping by the human DNA repair protein AGT

Nature Structural & Molecular Biology
Douglas S DanielsJohn A Tainer

Abstract

O(6)-alkylguanine-DNA alkyltransferase (AGT), or O(6)-methylguanine-DNA methyltransferase (MGMT), prevents mutations and apoptosis resulting from alkylation damage to guanines. AGT irreversibly transfers the alkyl lesion to an active site cysteine in a stoichiometric, direct damage reversal pathway. AGT expression therefore elicits tumor resistance to alkylating chemotherapies, and AGT inhibitors are in clinical trials. We report here structures of human AGT in complex with double-stranded DNA containing the biological substrate O(6)-methylguanine or crosslinked to the mechanistic inhibitor N(1),O(6)-ethanoxanthosine. The prototypical DNA major groove-binding helix-turn-helix (HTH) motif mediates unprecedented minor groove DNA binding. This binding architecture has advantages for DNA repair and nucleotide flipping, and provides a paradigm for HTH interactions in sequence-independent DNA-binding proteins like RecQ and BRCA2. Structural and biochemical results further support an unpredicted role for Tyr114 in nucleotide flipping through phosphate rotation and an efficient kinetic mechanism for locating alkylated bases.

References

Jan 1, 1988·Chemico-biological Interactions·A E PeggM E Dolan
Aug 1, 1988·Journal of Biomolecular Structure & Dynamics·R Lavery, H Sklenar
Apr 20, 1988·Journal of Molecular Biology·P C Moody, B Demple
Jan 1, 1993·Progress in Nucleic Acid Research and Molecular Biology·S Mitra, B Kaina
Mar 14, 1998·Carcinogenesis·W MeikrantzL Samson
Aug 26, 1998·Proceedings of the National Academy of Sciences of the United States of America·B J GlassnerL D Samson
Oct 3, 1998·Acta Crystallographica. Section D, Biological Crystallography·A T BrüngerG L Warren
Oct 27, 1998·Trends in Biochemical Sciences·G Dodson, A Wlodawer
Dec 3, 1999·Science·T Lindahl, R D Wood
Dec 22, 1999·Nucleic Acids Research·J E WibleyP C Moody
Feb 19, 2000·Current Opinion in Structural Biology·K S Gajiwala, S K Burley
Apr 12, 2000·European Journal of Biochemistry·G Frosina
Dec 2, 2000·The EMBO Journal·N P StanfordS E Halford
Dec 6, 2000·Genome Biology·N M LuscombeJ M Thornton
Nov 10, 2001·Nature Structural Biology·B L SibandaL Pellegrini
May 1, 2002·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Stanton L Gerson
Jun 8, 2002·Journal of Molecular Biology·Nilesh K Banavali, Alexander D MacKerell
Jul 3, 2002·Biochemistry·Kieu X LuuRobert C Moschel
Dec 24, 2002·The Journal of Biological Chemistry·Joseph J RasimasMichael G Fried
Dec 31, 2002·Proceedings of the National Academy of Sciences of the United States of America·Niu HuangAlexander D MacKerell
Sep 17, 2003·Biochemistry·F Peter GuengerichAnthony E Pegg
Oct 1, 2003·The EMBO Journal·Douglas A BernsteinJames L Keck
Jan 31, 2004·Proceedings of the National Academy of Sciences of the United States of America·James Holton, Tom Alber
Apr 8, 2004·Molecular Cell·Mark J Hickman, Leona D Samson
Sep 1, 1994·Acta Crystallographica. Section D, Biological Crystallography·UNKNOWN Collaborative Computational Project, Number 4

❮ Previous
Next ❯

Citations

May 27, 2010·Cellular and Molecular Life Sciences : CMLS·Julie L Tubbs, John A Tainer
Jan 10, 2012·Breast Cancer Research and Treatment·Caterina FumagalliMassimo Barberis
Jul 4, 2012·Journal of Biosciences·N R Jena
Sep 29, 2006·Clinical & Translational Oncology : Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico·Isabel Sánchez-Pérez
Jun 21, 2005·Journal of Molecular Biology·Erica M DuguidChuan He
Jun 9, 2005·Mutation Research·Joy L HuffmanJohn A Tainer
Jun 19, 2013·Trends in Biochemical Sciences·Gábor M HaramiMihály Kovács
Oct 24, 2009·Accounts of Chemical Research·Chengqi YiChuan He
Feb 9, 2006·Chemical Reviews·Yukiko MishinaChuan He
Feb 9, 2006·Chemical Reviews·Patrick J O'Brien
Aug 21, 2008·Chemical Research in Toxicology·Aley G KalapilaAnthony E Pegg
Jun 2, 2009·Chemical Research in Toxicology·Rachel L LoeberNatalia Y Tretyakova
Apr 15, 2008·Nature Structural & Molecular Biology·Elsa D GarcinJohn A Tainer
Jul 29, 2004·Nature Structural & Molecular Biology·Thomas J Begley, Leona D Samson
Mar 21, 2008·Proceedings of the National Academy of Sciences of the United States of America·Jie HuAaron R Dinner
Aug 2, 2008·Proceedings of the National Academy of Sciences of the United States of America·Rishi H Porecha, James T Stivers
Nov 1, 2012·Proceedings of the National Academy of Sciences of the United States of America·Oliver J WilkinsonDavid M Williams
Jun 18, 2009·The Journal of Biological Chemistry·Rebecca GuzaNatalia Tretyakova
Dec 23, 2009·The Journal of Biological Chemistry·Qingming FangAnthony E Pegg
Mar 10, 2010·The Journal of Biological Chemistry·James M AraminiGaetano T Montelione
Dec 15, 2011·The Journal of Biological Chemistry·Giuseppe PeruginoMaria Ciaramella
Dec 2, 2006·The Journal of Biological Chemistry·Joseph J RasimasMichael G Fried
Dec 7, 2007·Nucleosides, Nucleotides & Nucleic Acids·Ana R Hornillo-AraujoDavid M Williams
Dec 13, 2005·Nucleic Acids Research·Robert K NeelyAnita C Jones
Aug 29, 2006·Nucleic Acids Research·Michael P Killoran, James L Keck

❮ Previous
Next ❯

Related Concepts

Related Feeds

Breast Cancer: BRCA1 & BRCA2

Mutations involving BRCA1, found on chromosome 17, and BRCA2, found on chromosome 13, increase the risk for specific cancers, such as breast cancer. Discover the last research on breast cancer BRCA1 and BRCA2 here.

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis