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PDBsum entry 1qnt

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protein links
DNA repair PDB id
1qnt
Jmol
Contents
Protein chain
166 a.a. *
Waters ×174
* Residue conservation analysis
PDB id:
1qnt
Name: DNA repair
Title: X-ray structure of human o6alkylguanine-DNA alkyltransferase
Structure: Methylated-DNA--protein-cysteine methyltransferase. Chain: a. Synonym: 6-o-methylguanine-DNA methyltransferase. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
1.90Å     R-factor:   0.198     R-free:   0.221
Authors: J.E.A.Wibley,P.C.E.Moody
Key ref: J.E.Wibley et al. (2000). Crystal structure of the human O(6)-alkylguanine-DNA alkyltransferase. Nucleic Acids Res, 28, 393-401. PubMed id: 10606635 DOI: 10.1093/nar/28.2.393
Date:
20-Oct-99     Release date:   16-Dec-99    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P16455  (MGMT_HUMAN) -  Methylated-DNA--protein-cysteine methyltransferase
Seq:
Struc:
207 a.a.
166 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.1.1.63  - Methylated-DNA--[protein]-cysteine S-methyltransferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: DNA (containing 6-O-methylguanine) + protein L-cysteine = DNA (without 6-O-methylguanine) + protein S-methyl-L-cysteine
DNA (containing 6-O-methylguanine)
+ protein L-cysteine
= DNA (without 6-O-methylguanine)
+ protein S-methyl-L-cysteine
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     DNA repair   1 term 
  Biochemical function     catalytic activity     2 terms  

 

 
    reference    
 
 
DOI no: 10.1093/nar/28.2.393 Nucleic Acids Res 28:393-401 (2000)
PubMed id: 10606635  
 
 
Crystal structure of the human O(6)-alkylguanine-DNA alkyltransferase.
J.E.Wibley, A.E.Pegg, P.C.Moody.
 
  ABSTRACT  
 
The mutagenic and carcinogenic effects of simple alkylating agents are mainly due to O(6)-alkylation of guanine in DNA. This lesion results in transition mutations. In both prokaryotic and eukaryotic cells, repair is effected by direct reversal of the damage by a suicide protein, O(6)-alkylguanine-DNA alkyltransferase. The alkyltransferase removes the alkyl group to one of its own cysteine residues. However, this mechanism for preserving genomic integrity limits the effectiveness of certain alkylating anticancer agents. A high level of the alkyltransferase in many tumour cells renders them resistant to such drugs. Here we report the X-ray structure of the human alkyltransferase solved using the technique of multiple wavelength anomalous dispersion. This structure explains the markedly different specificities towards various O(6)-alkyl lesions and inhibitors when compared with the Escherichia coli protein (for which the structure has already been determined). It is also used to interpret the behaviour of certain mutant alkyltransferases to enhance biochemical understanding of the protein. Further examination of the various models proposed for DNA binding is also permitted. This structure may be useful for the design and refinement of drugs as chemoenhancers of alkylating agent chemotherapy.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20702424 J.A.Burns, K.Dreij, L.Cartularo, and D.A.Scicchitano (2010).
O6-methylguanine induces altered proteins at the level of transcription in human cells.
  Nucleic Acids Res, 38, 8178-8187.  
20502938 J.L.Tubbs, and J.A.Tainer (2010).
Alkyltransferase-like proteins: molecular switches between DNA repair pathways.
  Cell Mol Life Sci, 67, 3749-3762.  
20026607 Q.Fang, S.Kanugula, J.L.Tubbs, J.A.Tainer, and A.E.Pegg (2010).
Repair of O4-alkylthymine by O6-alkylguanine-DNA alkyltransferases.
  J Biol Chem, 285, 8185-8195.  
19164530 C.S.Hwang, A.Shemorry, and A.Varshavsky (2009).
Two proteolytic pathways regulate DNA repair by cotargeting the Mgt1 alkylguanine transferase.
  Proc Natl Acad Sci U S A, 106, 2142-2147.  
19516334 J.L.Tubbs, V.Latypov, S.Kanugula, A.Butt, M.Melikishvili, R.Kraehenbuehl, O.Fleck, A.Marriott, A.J.Watson, B.Verbeek, G.McGown, M.Thorncroft, M.F.Santibanez-Koref, C.Millington, A.S.Arvai, M.D.Kroeger, L.A.Peterson, D.M.Williams, M.G.Fried, G.P.Margison, A.E.Pegg, and J.A.Tainer (2009).
Flipping of alkylated DNA damage bridges base and nucleotide excision repair.
  Nature, 459, 808-813.
PDB codes: 3gva 3gx4 3gyh
18291317 A.Gautier, A.Juillerat, C.Heinis, I.R.Corrêa, M.Kindermann, F.Beaufils, and K.Johnsson (2008).
An engineered protein tag for multiprotein labeling in living cells.
  Chem Biol, 15, 128-136.  
18353991 J.Hu, A.Ma, and A.R.Dinner (2008).
A two-step nucleotide-flipping mechanism enables kinetic discrimination of DNA lesions by AGT.
  Proc Natl Acad Sci U S A, 105, 4615-4620.  
18803403 Q.Fang, A.M.Noronha, S.P.Murphy, C.J.Wilds, J.L.Tubbs, J.A.Tainer, G.Chowdhury, F.P.Guengerich, and A.E.Pegg (2008).
Repair of O6-G-alkyl-O6-G interstrand cross-links by human O6-alkylguanine-DNA alkyltransferase.
  Biochemistry, 47, 10892-10903.  
17482892 A.E.Pegg, Q.Fang, and N.A.Loktionova (2007).
Human variants of O6-alkylguanine-DNA alkyltransferase.
  DNA Repair (Amst), 6, 1071-1078.  
17485252 J.L.Tubbs, A.E.Pegg, and J.A.Tainer (2007).
DNA binding, nucleotide flipping, and the helix-turn-helix motif in base repair by O6-alkylguanine-DNA alkyltransferase and its implications for cancer chemotherapy.
  DNA Repair (Amst), 6, 1100-1115.  
17880193 S.Javanmard, N.A.Loktionova, Q.Fang, G.T.Pauly, A.E.Pegg, and R.C.Moschel (2007).
Inactivation of O(6)-alkylguanine-DNA alkyltransferase by folate esters of O(6)-benzyl-2'-deoxyguanosine and of O(6)-[4-(hydroxymethyl)benzyl]guanine.
  J Med Chem, 50, 5193-5201.  
  17591937 T.Mikeska, C.Bock, O.El-Maarri, A.Hübner, D.Ehrentraut, J.Schramm, J.Felsberg, P.Kahl, R.Büttner, T.Pietsch, and A.Waha (2007).
Optimization of quantitative MGMT promoter methylation analysis using pyrosequencing and combined bisulfite restriction analysis.
  J Mol Diagn, 9, 368-381.  
16633564 A.R.Hornillo-Araujo, A.J.Burrell, M.K.Aiertza, T.Shibata, D.M.Hammond, D.Edmont, H.Adams, G.P.Margison, and D.M.Williams (2006).
The syntheses and properties of tricyclic pyrrolo[2,3-d]pyrimidine analogues of S6-methylthioguanine and O6-methylguanine.
  Org Biomol Chem, 4, 1723-1729.  
16826543 A.Roberts, J.G.Pelton, and D.E.Wemmer (2006).
Structural studies of MJ1529, an O6-methylguanine-DNA methyltransferase.
  Magn Reson Chem, 44, S71-S82.
PDB code: 2g7h
16698182 C.A.Rabik, M.C.Njoku, and M.E.Dolan (2006).
Inactivation of O6-alkylguanine DNA alkyltransferase as a means to enhance chemotherapy.
  Cancer Treat Rev, 32, 261-276.  
16464003 Y.Mishina, E.M.Duguid, and C.He (2006).
Direct reversal of DNA alkylation damage.
  Chem Rev, 106, 215-232.  
15934048 A.Juillerat, C.Heinis, I.Sielaff, J.Barnikow, H.Jaccard, B.Kunz, A.Terskikh, and K.Johnsson (2005).
Engineering substrate specificity of O6-alkylguanine-DNA alkyltransferase for specific protein labeling in living cells.
  Chembiochem, 6, 1263-1269.  
16201908 L.Benimetskaya, P.Miller, and C.A.Stein (2005).
518A2 melanoma cells are protected by G3139 and other antineoplastic agents against the cytotoxic effects of DTIC.
  Oligonucleotides, 15, 206-214.  
15731349 S.Kanugula, G.T.Pauly, R.C.Moschel, and A.E.Pegg (2005).
A bifunctional DNA repair protein from Ferroplasma acidarmanus exhibits O6-alkylguanine-DNA alkyltransferase and endonuclease V activities.
  Proc Natl Acad Sci U S A, 102, 3617-3622.  
15040447 B.Sedgwick (2004).
Repairing DNA-methylation damage.
  Nat Rev Mol Cell Biol, 5, 148-157.  
15221026 D.S.Daniels, T.T.Woo, K.X.Luu, D.M.Noll, N.D.Clarke, A.E.Pegg, and J.A.Tainer (2004).
DNA binding and nucleotide flipping by the human DNA repair protein AGT.
  Nat Struct Mol Biol, 11, 714-720.
PDB codes: 1t38 1t39
15057289 S.L.Gerson (2004).
MGMT: its role in cancer aetiology and cancer therapeutics.
  Nat Rev Cancer, 4, 296-307.  
12725859 A.Juillerat, T.Gronemeyer, A.Keppler, S.Gendreizig, H.Pick, H.Vogel, and K.Johnsson (2003).
Directed evolution of O6-alkylguanine-DNA alkyltransferase for efficient labeling of fusion proteins with small molecules in vivo.
  Chem Biol, 10, 313-317.  
14522053 E.M.Duguid, Y.Mishina, and C.He (2003).
How do DNA repair proteins locate potential base lesions? a chemical crosslinking method to investigate O6-alkylguanine-DNA alkyltransferases.
  Chem Biol, 10, 827-835.  
  11574685 D.M.Noll, and N.D.Clarke (2001).
Covalent capture of a human O(6)-alkylguanine alkyltransferase-DNA complex using N(1),O(6)-ethanoxanthosine, a mechanism-based crosslinker.
  Nucleic Acids Res, 29, 4025-4034.  
11732917 J.C.Delaney, and J.M.Essigmann (2001).
Effect of sequence context on O(6)-methylguanine repair and replication in vivo.
  Biochemistry, 40, 14968-14975.  
11746760 S.Kanugula, and A.E.Pegg (2001).
Novel DNA repair alkyltransferase from Caenorhabditis elegans.
  Environ Mol Mutagen, 38, 235-243.  
10747039 D.S.Daniels, C.D.Mol, A.S.Arvai, S.Kanugula, A.E.Pegg, and J.A.Tainer (2000).
Active and alkylated human AGT structures: a novel zinc site, inhibitor and extrahelical base binding.
  EMBO J, 19, 1719-1730.
PDB codes: 1eh6 1eh7 1eh8
11000262 P.E.Verdemato, J.A.Brannigan, C.Damblon, F.Zuccotto, P.C.Moody, and L.Y.Lian (2000).
DNA-binding mechanism of the Escherichia coli Ada O(6)-alkylguanine-DNA alkyltransferase.
  Nucleic Acids Res, 28, 3710-3718.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.