PDBsum entry 2o3c

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protein metals Protein-protein interface(s) links
DNA binding protein PDB id
Protein chains
276 a.a. *
_PB ×3
Waters ×362
* Residue conservation analysis
PDB id:
Name: DNA binding protein
Title: Crystal structure of zebrafish ape
Structure: Apex nuclease 1. Chain: a, b, c. Synonym: apurinic/apyrimidinic endonuclease. Engineered: yes
Source: Danio rerio. Zebrafish. Organism_taxid: 7955. Gene: apex1. Expressed in: escherichia coli. Expression_system_taxid: 562.
2.30Å     R-factor:   0.199     R-free:   0.236
Authors: M.M.Georgiadis,R.K.Gaur,S.Delaplane,J.Svenson
Key ref: M.M.Georgiadis et al. (2008). Evolution of the redox function in mammalian apurinic/apyrimidinic endonuclease. Mutat Res, 643, 54-63. PubMed id: 18579163
01-Dec-06     Release date:   11-Dec-07    
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Protein chains
Pfam   ArchSchema ?
A0MTA1  (APEX1_DANRE) -  DNA-(apurinic or apyrimidinic site) lyase
310 a.a.
276 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.  - DNA-(apurinic or apyrimidinic site) lyase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: The C-O-P bond 3' to the apurinic or apyrimidinic site in DNA is broken by a beta-elimination reaction, leaving a 3'-terminal unsaturated sugar and a product with a terminal 5'-phosphate.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     intracellular   7 terms 
  Biological process     nucleic acid phosphodiester bond hydrolysis   5 terms 
  Biochemical function     hydrolase activity     8 terms  


Mutat Res 643:54-63 (2008)
PubMed id: 18579163  
Evolution of the redox function in mammalian apurinic/apyrimidinic endonuclease.
M.M.Georgiadis, M.Luo, R.K.Gaur, S.Delaplane, X.Li, M.R.Kelley.
Human apurinic/apyrimidinic endonuclease (hApe1) encodes two important functional activities: an essential base excision repair (BER) activity and a redox activity that regulates expression of a number of genes through reduction of their transcription factors, AP-1, NFkappaB, HIF-1alpha, CREB, p53 and others. The BER function is highly conserved from prokaryotes (E. coli exonuclease III) to humans (hApe1). Here, we provide evidence supporting a redox function unique to mammalian Apes. An evolutionary analysis of Ape sequences reveals that, of the 7 Cys residues, Cys 93, 99, 208, 296, and 310 are conserved in both mammalian and non-mammalian vertebrate Apes, while Cys 65 is unique to mammalian Apes. In the zebrafish Ape (zApe), selected as the vertebrate sequence most distant from human, the residue equivalent to Cys 65 is Thr 58. The wild-type zApe enzyme was tested for redox activity in both in vitro EMSA and transactivation assays and found to be inactive, similar to C65A hApe1. Substitution of Thr 58 with Cys in zApe, however, resulted in a redox active enzyme, suggesting that a Cys residue in this position is indeed critical for redox function. In order to further probe differences between redox active and inactive enzymes, we have determined the crystal structures of vertebrate redox inactive enzymes, the C65A human Ape1 enzyme and the zApe enzyme at 1.9 and 2.3A, respectively. Our results provide new insights on the redox function and highlight a dramatic gain-of-function activity for Ape1 in mammals not found in non-mammalian vertebrates or lower organisms.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21353648 D.O.Onyango, A.Naguleswaran, S.Delaplane, A.Reed, M.R.Kelley, M.M.Georgiadis, and W.J.Sullivan (2011).
Base excision repair apurinic/apyrimidinic endonucleases in apicomplexan parasite Toxoplasma gondii.
  DNA Repair (Amst), 10, 466-475.  
21172930 D.S.Pei, X.J.Yang, W.Liu, J.E.Guikema, C.E.Schrader, and P.R.Strauss (2011).
A novel regulatory circuit in base excision repair involving AP endonuclease 1, Creb1 and DNA polymerase beta.
  Nucleic Acids Res, 39, 3156-3165.  
20874257 M.R.Kelley, M.Luo, A.Reed, D.Su, S.Delaplane, R.F.Borch, R.L.Nyland, M.L.Gross, and M.M.Georgiadis (2011).
Functional analysis of novel analogues of E3330 that block the redox signaling activity of the multifunctional AP endonuclease/redox signaling enzyme APE1/Ref-1.
  Antioxid Redox Signal, 14, 1387-1401.  
20711647 C.S.Busso, M.W.Lake, and T.Izumi (2010).
Posttranslational modification of mammalian AP endonuclease (APE1).
  Cell Mol Life Sci, 67, 3609-3620.  
20699270 D.Fantini, C.Vascotto, D.Marasco, C.D'Ambrosio, M.Romanello, L.Vitagliano, C.Pedone, M.Poletto, L.Cesaratto, F.Quadrifoglio, A.Scaloni, J.P.Radicella, and G.Tell (2010).
Critical lysine residues within the overlooked N-terminal domain of human APE1 regulate its biological functions.
  Nucleic Acids Res, 38, 8239-8256.  
20706766 G.Tell, D.Fantini, and F.Quadrifoglio (2010).
Understanding different functions of mammalian AP endonuclease (APE1) as a promising tool for cancer treatment.
  Cell Mol Life Sci, 67, 3589-3608.  
20446770 J.Shlomai (2010).
Redox control of protein-DNA interactions: from molecular mechanisms to significance in signal transduction, gene expression, and DNA replication.
  Antioxid Redox Signal, 13, 1429-1476.  
19764832 M.Luo, H.He, M.R.Kelley, and M.M.Georgiadis (2010).
Redox regulation of DNA repair: implications for human health and cancer therapeutic development.
  Antioxid Redox Signal, 12, 1247-1269.  
20067291 R.L.Nyland, M.Luo, M.R.Kelley, and R.F.Borch (2010).
Design and synthesis of novel quinone inhibitors targeted to the redox function of apurinic/apyrimidinic endonuclease 1/redox enhancing factor-1 (Ape1/ref-1).
  J Med Chem, 53, 1200-1210.  
18976116 G.Tell, F.Quadrifoglio, C.Tiribelli, and M.R.Kelley (2009).
The many functions of APE1/Ref-1: not only a DNA repair enzyme.
  Antioxid Redox Signal, 11, 601-620.  
19726241 Y.Jiang, C.Guo, M.L.Fishel, Z.Y.Wang, M.R.Vasko, and M.R.Kelley (2009).
Role of APE1 in differentiated neuroblastoma SH-SY5Y cells in response to oxidative stress: use of APE1 small molecule inhibitors to delineate APE1 functions.
  DNA Repair (Amst), 8, 1273-1282.  
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