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High-resolution crystal structures reveal plasticity in the metal binding site of apurinic/apyrimidinic endonuclease I.

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He H, Chen Q, Georgiadis MM
OpenAccess logo Biochemistry 53 6520-9 (2014)
Related entries: 4qh9, 4qhd

Cited: 34 times
EuropePMC logo PMID: 25251148

Abstract

Apurinic/apyrimidinic endonuclease I (APE1) is an essential base excision repair enzyme that catalyzes a Mg²⁺-dependent reaction in which the phosphodiester backbone is cleaved 5' of an abasic site in duplex DNA. This reaction has been proposed to involve either one or two metal ions bound to the active site. In the present study, we report crystal structures of Mg²⁺, Mn²⁺, and apo-APE1 determined at 1.4, 2.2, and 1.65 Å, respectively, representing two of the highest resolution structures yet reported for APE1. In our structures, a single well-ordered Mn²⁺ ion was observed coordinated by D70 and E96; the Mg²⁺ site exhibited disorder modeled as two closely positioned sites coordinated by D70 and E96 or E96 alone. Direct metal binding analysis of wild-type, D70A, and E96A APE1, as assessed by differential scanning fluorimetry, indicated a role for D70 and E96 in binding of Mg²⁺ or Mn²⁺ to APE1. Consistent with the disorder exhibited by Mg²⁺ bound to the active site, two different conformations of E96 were observed coordinated to Mg²⁺. A third conformation for E96 in the apo structure is similar to that observed in the APE1-DNA-Mg²⁺ complex structure. Thus, binding of Mg²⁺ in three different positions within the active site of APE1 in these crystal structures corresponds directly with three different conformations of E96. Taken together, our results are consistent with the initial capture of metal by D70 and E96 and repositioning of Mg²⁺ facilitated by the structural plasticity of E96 in the active site.

Reviews - 4qhe mentioned but not cited (1)

  1. Molecular Mechanisms Regulating the DNA Repair Protein APE1: A Focus on Its Flexible N-Terminal Tail Domain. López DJ, Rodríguez JA, Bañuelos S. Int J Mol Sci 22 6308 (2021)

Articles - 4qhe mentioned but not cited (9)

  1. Capturing snapshots of APE1 processing DNA damage. Freudenthal BD, Beard WA, Cuneo MJ, Dyrkheeva NS, Wilson SH. Nat Struct Mol Biol 22 924-931 (2015)
  2. High-resolution crystal structures reveal plasticity in the metal binding site of apurinic/apyrimidinic endonuclease I. He H, Chen Q, Georgiadis MM. Biochemistry 53 6520-6529 (2014)
  3. Fragment- and structure-based drug discovery for developing therapeutic agents targeting the DNA Damage Response. Wilson DM, Deacon AM, Duncton MAJ, Pellicena P, Georgiadis MM, Yeh AP, Arvai AS, Moiani D, Tainer JA, Das D. Prog Biophys Mol Biol 163 130-142 (2021)
  4. An APE1 inhibitor reveals critical roles of the redox function of APE1 in KSHV replication and pathogenic phenotypes. Zhong C, Xu M, Wang Y, Xu J, Yuan Y. PLoS Pathog 13 e1006289 (2017)
  5. Two distinct mechanisms of transcriptional regulation by the redox sensor YodB. Lee SJ, Lee IG, Lee KY, Kim DG, Eun HJ, Yoon HJ, Chae S, Song SH, Kang SO, Seo MD, Kim HS, Park SJ, Lee BJ. Proc Natl Acad Sci U S A 113 E5202-11 (2016)
  6. In Silico Insight into Potential Anti-Alzheimer's Disease Mechanisms of Icariin. Cui Z, Sheng Z, Yan X, Cao Z, Tang K. Int J Mol Sci 17 E113 (2016)
  7. Bioinformatic Prediction of Signaling Pathways for Apurinic/Apyrimidinic Endodeoxyribonuclease 1 (APEX1) and Its Role in Cholangiocarcinoma Cells. Tummanatsakun D, Proungvitaya T, Roytrakul S, Proungvitaya S. Molecules 26 2587 (2021)
  8. Cadmium(II) inhibition of human uracil-DNA glycosylase by catalytic water supplantation. Gokey T, Hang B, Guliaev AB. Sci Rep 6 39137 (2016)
  9. Highly Accessible Computational Prediction and In Vivo/In Vitro Experimental Validation: Novel Synthetic Phenyl Ketone Derivatives as Promising Agents against NAFLD via Modulating Oxidoreductase Activity. Qiao Y, Deng H, Liu L, Liu S, Ren L, Shi C, Chen X, Guan L, Liu W, Li Z, Li Y. Oxid Med Cell Longev 2023 3782230 (2023)


Reviews citing this publication (2)

  1. Inhibition of APE1/Ref-1 for Neovascular Eye Diseases: From Biology to Therapy. Hartman GD, Lambert-Cheatham NA, Kelley MR, Corson TW. Int J Mol Sci 22 10279 (2021)
  2. Understanding APE1 cellular functions by the structural preference of exonuclease activities. Liu TC, Guo KW, Chu JW, Hsiao YY. Comput Struct Biotechnol J 19 3682-3691 (2021)

Articles citing this publication (22)

  1. Molecular snapshots of APE1 proofreading mismatches and removing DNA damage. Whitaker AM, Flynn TS, Freudenthal BD. Nat Commun 9 399 (2018)
  2. The activating oxydianion binding domain for enzyme-catalyzed proton transfer, hydride transfer, and decarboxylation: specificity and enzyme architecture. Reyes AC, Zhai X, Morgan KT, Reinhardt CJ, Amyes TL, Richard JP. J Am Chem Soc 137 1372-1382 (2015)
  3. Effects of mono- and divalent metal ions on DNA binding and catalysis of human apurinic/apyrimidinic endonuclease 1. Miroshnikova AD, Kuznetsova AA, Vorobjev YN, Kuznetsov NA, Fedorova OS. Mol Biosyst 12 1527-1539 (2016)
  4. AP-endonuclease 1 sculpts DNA through an anchoring tyrosine residue on the DNA intercalating loop. Hoitsma NM, Whitaker AM, Beckwitt EC, Jang S, Agarwal PK, Van Houten B, Freudenthal BD. Nucleic Acids Res 48 7345-7355 (2020)
  5. The major Arabidopsis thaliana apurinic/apyrimidinic endonuclease, ARP is involved in the plant nucleotide incision repair pathway. Akishev Z, Taipakova S, Joldybayeva B, Zutterling C, Smekenov I, Ishchenko AA, Zharkov DO, Bissenbaev AK, Saparbaev M. DNA Repair (Amst) 48 30-42 (2016)
  6. Viral genome packaging terminase cleaves DNA using the canonical RuvC-like two-metal catalysis mechanism. Xu RG, Jenkins HT, Chechik M, Blagova EV, Lopatina A, Klimuk E, Minakhin L, Severinov K, Greive SJ, Antson AA. Nucleic Acids Res 45 3580-3590 (2017)
  7. Effect of the Substrate Structure and Metal Ions on the Hydrolysis of Undamaged RNA by Human AP Endonuclease APE1. Kuznetsova AA, Novopashina DS, Fedorova OS, Kuznetsov NA. Acta Naturae 12 74-85 (2020)
  8. Discovery of Macrocyclic Inhibitors of Apurinic/Apyrimidinic Endonuclease 1. Trilles R, Beglov D, Chen Q, He H, Wireman R, Reed A, Chennamadhavuni S, Panek JS, Brown LE, Vajda S, Porco JA, Kelley MR, Georgiadis MM. J Med Chem 62 1971-1988 (2019)
  9. Small molecule activation of apurinic/apyrimidinic endonuclease 1 reduces DNA damage induced by cisplatin in cultured sensory neurons. Georgiadis MM, Chen Q, Meng J, Guo C, Wireman R, Reed A, Vasko MR, Kelley MR. DNA Repair (Amst) 41 32-41 (2016)
  10. Mutational and Kinetic Analysis of APE1 Endoribonuclease Activity. Kuznetsova AA, Gavrilova AA, Novopashina DS, Fedorova OS, Kuznetsov NA. Mol Biol 55 211-224 (2021)
  11. Role of AP-endonuclease (Ape1) active site residues in stabilization of the reactant enzyme-DNA complex. Batebi H, Dragelj J, Imhof P. Proteins 86 439-453 (2018)
  12. The Enigma of Substrate Recognition and Catalytic Efficiency of APE1-Like Enzymes. Davletgildeeva AT, Ishchenko AA, Saparbaev M, Fedorova OS, Kuznetsov NA. Front Cell Dev Biol 9 617161 (2021)
  13. Altered APE1 activity on abasic ribonucleotides is mediated by changes in the nucleoside sugar pucker. Hoitsma NM, Click TH, Agarwal PK, Freudenthal BD. Comput Struct Biotechnol J 19 3293-3302 (2021)
  14. Characterizing inhibitors of human AP endonuclease 1. Pidugu LS, Servius HW, Sevdalis SE, Cook ME, Varney KM, Pozharski E, Drohat AC. PLoS One 18 e0280526 (2023)
  15. Structural dissection of sequence recognition and catalytic mechanism of human LINE-1 endonuclease. Miller I, Totrov M, Korotchkina L, Kazyulkin DN, Gudkov AV, Korolev S. Nucleic Acids Res 49 11350-11366 (2021)
  16. Comparative Analysis of Exo- and Endonuclease Activities of APE1-like Enzymes. Davletgildeeva AT, Kuznetsova AA, Novopashina DS, Ishchenko AA, Saparbaev M, Fedorova OS, Kuznetsov NA. Int J Mol Sci 23 2869 (2022)
  17. Processing oxidatively damaged bases at DNA strand breaks by APE1. Whitaker AM, Stark WJ, Freudenthal BD. Nucleic Acids Res 50 9521-9533 (2022)
  18. Structural dynamics of wild type and mutated forms of human L1 endonuclease and insights into its sequence specific nucleic acid binding mechanism: A molecular dynamics study. Rajagopalan M, Balasubramanian S, Ramaswamy A. J Mol Graph Model 76 43-55 (2017)
  19. AUF1 Recognizes 8-Oxo-Guanosine Embedded in DNA and Stimulates APE1 Endoribonuclease Activity. Malfatti MC, Codrich M, Dalla E, D'Ambrosio C, Storici F, Scaloni A, Tell G. Antioxid Redox Signal 39 411-431 (2023)
  20. Characterization of biochemical properties of an apurinic/apyrimidinic endonuclease from Helicobacter pylori. Turgimbayeva A, Abeldenov S, Zharkov DO, Ishchenko AA, Ramankulov Y, Saparbaev M, Khassenov B. PLoS One 13 e0202232 (2018)
  21. A New Drug Discovery Platform: Application to DNA Polymerase Eta and Apurinic/Apyrimidinic Endonuclease 1. Das D, Duncton MAJ, Georgiadis TM, Pellicena P, Clark J, Sobol RW, Georgiadis MM, King-Underwood J, Jobes DV, Chang C, Gao Y, Deacon AM, Wilson DM. Int J Mol Sci 24 16637 (2023)
  22. Mechanistic insight into AP-endonuclease 1 cleavage of abasic sites at stalled replication fork mimics. Hoitsma NM, Norris J, Khoang TH, Kaushik V, Chadda R, Antony E, Hedglin M, Freudenthal BD. Nucleic Acids Res 51 6738-6753 (2023)


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