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PDBsum entry 1mq2

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protein dna_rna ligands metals links
Transferase/DNA PDB id
1mq2
Jmol PyMol
Contents
Protein chain
326 a.a. *
DNA/RNA
Ligands
_DA
Metals
_NA ×2
Waters ×4
* Residue conservation analysis
PDB id:
1mq2
Name: Transferase/DNA
Title: Human DNA polymerase beta complexed with gapped DNA containing an 8-oxo-7,8-dihydro-guanine and damp
Structure: 5'-d( Cp Cp Gp Ap Cp (8Og) p Tp Cp Gp Cp Ap Tp Cp Ap Gp C)-3'. Chain: t. Engineered: yes. 5'-d( Gp Cp Tp Gp Ap Tp Gp Cp Gp (2Da))-3'. Chain: p. Engineered: yes. 5'-d(p Gp Tp Cp Gp G)-3'. Chain: d.
Source: Synthetic: yes. Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
Biol. unit: Tetramer (from PQS)
Resolution:
3.10Å     R-factor:   0.257     R-free:   0.317
Authors: J.M.Krahn,W.A.Beard,H.Miller,A.P.Grollman,S.H.Wilson
Key ref:
J.M.Krahn et al. (2003). Structure of DNA polymerase beta with the mutagenic DNA lesion 8-oxodeoxyguanine reveals structural insights into its coding potential. Structure, 11, 121-127. PubMed id: 12517346 DOI: 10.1016/S0969-2126(02)00930-9
Date:
13-Sep-02     Release date:   28-Jan-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P06746  (DPOLB_HUMAN) -  DNA polymerase beta
Seq:
Struc:
335 a.a.
326 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     protein complex   6 terms 
  Biological process     immunoglobulin heavy chain V-D-J recombination   27 terms 
  Biochemical function     protein binding     12 terms  

 

 
DOI no: 10.1016/S0969-2126(02)00930-9 Structure 11:121-127 (2003)
PubMed id: 12517346  
 
 
Structure of DNA polymerase beta with the mutagenic DNA lesion 8-oxodeoxyguanine reveals structural insights into its coding potential.
J.M.Krahn, W.A.Beard, H.Miller, A.P.Grollman, S.H.Wilson.
 
  ABSTRACT  
 
Oxidative damage to DNA generates 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG). During DNA replication and repair synthesis, 8-oxodG can pair with cytosine or adenine. The ability to accurately replicate through this lesion depends on the DNA polymerase. We report the first structure of a polymerase with a promutagenic DNA lesion, 8-oxodG, in the confines of its active site. The modified guanine residue is in an anti conformation and forms Watson-Crick hydrogen bonds with an incoming dCTP. To accommodate the oxygen at C8, the 5'-phosphate backbone of the templating nucleotide flips 180 degrees. Thus, the flexibility of the template sugar-phosphate backbone near the polymerase active site is one parameter that influences the anti-syn equilibrium of 8-oxodG. Our results provide insights into the mechanisms employed by polymerases to select the complementary dNTP.
 
  Selected figure(s)  
 
Figure 3.
Figure 3. DNA Polymerase b Ternary Complex with 8-OxodG-dCTP(A) 2F[o] - F[c] electron density map contoured at 1 s (black), superimposed on the refined model. Additionally, a difference map was calculated, omitting O8 and contoured at 3.3 s. Negative density (red) is visible at the 8-oxy position of the template base, demonstrating unbiased evidence of the presence of the additional oxygen. The ternary complex with an 8-oxodG template base is very similar to the previously determined ternary complex containing undamaged deoxyguanine paired with ddCTP [12]. The modified guanine is in the standard anti conformation, and dCTP is bound with a coordinating Mg2+ atom (data not shown).(B) Comparison of the 5'-phosphate backbone conformation of 8-oxodG relative to that observed in the structure of pol b with an unmodified deoxyguanine in the polymerase active site (orange) [12]. The presence of the sharp bend along with limited enzyme contacts with this phosphate enables flipping of the phosphate away from the carbonyl oxygen at C8 of 8-oxodG. The backbone a torsion angle (O3'-P-O5'-C5') of the templating guanine is altered 184 when a carbonyl group is introduced at C8. In addition, the Lys280 side chain position, but not that of Asp276, is altered in the presence of 8-oxodG.
 
  The above figure is reprinted by permission from Cell Press: Structure (2003, 11, 121-127) copyright 2003.  
  Figure was selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20411947 J.Beckman, M.Wang, G.Blaha, J.Wang, and W.H.Konigsberg (2010).
Substitution of Ala for Tyr567 in RB69 DNA polymerase allows dAMP to be inserted opposite 7,8-dihydro-8-oxoguanine .
  Biochemistry, 49, 4116-4125.
PDB codes: 3lzi 3lzj
19631767 J.Yamtich, and J.B.Sweasy (2010).
DNA polymerase family X: function, structure, and cellular roles.
  Biochim Biophys Acta, 1804, 1136-1150.  
20166748 M.Hogg, J.Rudnicki, J.Midkiff, L.Reha-Krantz, S.Doublié, and S.S.Wallace (2010).
Kinetics of mismatch formation opposite lesions by the replicative DNA polymerase from bacteriophage RB69.
  Biochemistry, 49, 2317-2325.
PDB code: 3lds
20540060 M.Winnacker, V.Welzmiller, R.Strasser, and T.Carell (2010).
Development of a DNA photoaffinity probe for the analysis of 8-OxodG-binding proteins in a human proteome.
  Chembiochem, 11, 1345-1349.  
20844920 S.H.Wilson, W.A.Beard, D.D.Shock, V.K.Batra, N.A.Cavanaugh, R.Prasad, E.W.Hou, Y.Liu, K.Asagoshi, J.K.Horton, D.F.Stefanick, P.S.Kedar, M.J.Carrozza, A.Masaoka, and M.L.Heacock (2010).
Base excision repair and design of small molecule inhibitors of human DNA polymerase β.
  Cell Mol Life Sci, 67, 3633-3647.  
21070945 T.D.Silverstein, R.Jain, R.E.Johnson, L.Prakash, S.Prakash, and A.K.Aggarwal (2010).
Structural basis for error-free replication of oxidatively damaged DNA by yeast DNA polymerase η.
  Structure, 18, 1463-1470.
PDB codes: 3oha 3ohb
20526335 V.K.Batra, W.A.Beard, E.W.Hou, L.C.Pedersen, R.Prasad, and S.H.Wilson (2010).
Mutagenic conformation of 8-oxo-7,8-dihydro-2'-dGTP in the confines of a DNA polymerase active site.
  Nat Struct Mol Biol, 17, 889-890.
PDB code: 3mby
19361427 F.Faucher, S.M.Robey-Bond, S.S.Wallace, and S.Doublié (2009).
Structural characterization of Clostridium acetobutylicum 8-oxoguanine DNA glycosylase in its apo form and in complex with 8-oxodeoxyguanosine.
  J Mol Biol, 387, 669-679.
PDB codes: 3f0z 3f10
19747886 F.Faucher, S.S.Wallace, and S.Doublié (2009).
Structural basis for the lack of opposite base specificity of Clostridium acetobutylicum 8-oxoguanine DNA glycosylase.
  DNA Repair (Amst), 8, 1283-1289.
PDB codes: 3i0w 3i0x
19758983 G.E.Damsma, and P.Cramer (2009).
Molecular basis of transcriptional mutagenesis at 8-oxoguanine.
  J Biol Chem, 284, 31658-31663.
PDB codes: 3i4m 3i4n
19446528 O.Rechkoblit, L.Malinina, Y.Cheng, N.E.Geacintov, S.Broyde, and D.J.Patel (2009).
Impact of conformational heterogeneity of OxoG lesions and their pairing partners on bypass fidelity by Y family polymerases.
  Structure, 17, 725-736.
PDB codes: 3gii 3gij 3gik 3gil 3gim
19492058 R.Vasquez-Del Carpio, T.D.Silverstein, S.Lone, M.K.Swan, J.R.Choudhury, R.E.Johnson, S.Prakash, L.Prakash, and A.K.Aggarwal (2009).
Structure of human DNA polymerase kappa inserting dATP opposite an 8-OxoG DNA lesion.
  PLoS One, 4, e5766.
PDB code: 3in5
19282446 S.D.McCulloch, R.J.Kokoska, P.Garg, P.M.Burgers, and T.A.Kunkel (2009).
The efficiency and fidelity of 8-oxo-guanine bypass by DNA polymerases delta and eta.
  Nucleic Acids Res, 37, 2830-2840.  
19200715 S.Schneider, S.Schorr, and T.Carell (2009).
Crystal structure analysis of DNA lesion repair and tolerance mechanisms.
  Curr Opin Struct Biol, 19, 87-95.  
19759017 W.A.Beard, D.D.Shock, V.K.Batra, L.C.Pedersen, and S.H.Wilson (2009).
DNA polymerase beta substrate specificity: side chain modulation of the "A-rule".
  J Biol Chem, 284, 31680-31689.
PDB codes: 3isb 3isc 3isd
18072751 J.C.Delaney, and J.M.Essigmann (2008).
Biological properties of single chemical-DNA adducts: a twenty year perspective.
  Chem Res Toxicol, 21, 232-252.  
18471977 V.K.Batra, W.A.Beard, D.D.Shock, L.C.Pedersen, and S.H.Wilson (2008).
Structures of DNA polymerase beta with active-site mismatches suggest a transient abasic site intermediate during misincorporation.
  Mol Cell, 30, 315-324.
PDB codes: 3c2k 3c2l 3c2m
18276636 Z.F.Pursell, J.T.McDonald, C.K.Mathews, and T.A.Kunkel (2008).
Trace amounts of 8-oxo-dGTP in mitochondrial dNTP pools reduce DNA polymerase gamma replication fidelity.
  Nucleic Acids Res, 36, 2174-2181.  
17631059 A.F.Moon, M.Garcia-Diaz, V.K.Batra, W.A.Beard, K.Bebenek, T.A.Kunkel, S.H.Wilson, and L.C.Pedersen (2007).
The X family portrait: structural insights into biological functions of X family polymerases.
  DNA Repair (Amst), 6, 1709-1725.  
17439962 G.C.Lin, J.Jaeger, and J.B.Sweasy (2007).
Loop II of DNA polymerase beta is important for polymerization activity and fidelity.
  Nucleic Acids Res, 35, 2924-2935.  
17507928 G.Maga, G.Villani, E.Crespan, U.Wimmer, E.Ferrari, B.Bertocci, and U.Hübscher (2007).
8-oxo-guanine bypass by human DNA polymerases in the presence of auxiliary proteins.
  Nature, 447, 606-608.  
17725985 M.A.Graziewicz, R.J.Bienstock, and W.C.Copeland (2007).
The DNA polymerase gamma Y955C disease variant associated with PEO and parkinsonism mediates the incorporation and translesion synthesis opposite 7,8-dihydro-8-oxo-2'-deoxyguanosine.
  Hum Mol Genet, 16, 2729-2739.  
18496613 M.Garcia-Diaz, and K.Bebenek (2007).
Multiple functions of DNA polymerases.
  CRC Crit Rev Plant Sci, 26, 105-122.  
17581577 S.S.David, V.L.O'Shea, and S.Kundu (2007).
Base-excision repair of oxidative DNA damage.
  Nature, 447, 941-950.  
17293403 Y.Wang, S.Reddy, W.A.Beard, S.H.Wilson, and T.Schlick (2007).
Differing conformational pathways before and after chemistry for insertion of dATP versus dCTP opposite 8-oxoG in DNA polymerase beta.
  Biophys J, 92, 3063-3070.  
17313689 Y.Wang, and T.Schlick (2007).
Distinct energetics and closing pathways for DNA polymerase beta with 8-oxoG template and different incoming nucleotides.
  BMC Struct Biol, 7, 7.  
16306039 H.Zang, A.Irimia, J.Y.Choi, K.C.Angel, L.V.Loukachevitch, M.Egli, and F.P.Guengerich (2006).
Efficient and high fidelity incorporation of dCTP opposite 7,8-dihydro-8-oxodeoxyguanosine by Sulfolobus solfataricus DNA polymerase Dpo4.
  J Biol Chem, 281, 2358-2372.
PDB codes: 2c22 2c28 2c2d 2c2e 2c2r
17005553 J.W.Hanes, D.M.Thal, and K.A.Johnson (2006).
Incorporation and replication of 8-oxo-deoxyguanosine by the human mitochondrial DNA polymerase.
  J Biol Chem, 281, 36241-36248.  
16679449 M.A.Kalam, K.Haraguchi, S.Chandani, E.L.Loechler, M.Moriya, M.M.Greenberg, and A.K.Basu (2006).
Genetic effects of oxidative DNA damages: comparative mutagenesis of the imidazole ring-opened formamidopyrimidines (Fapy lesions) and 8-oxo-purines in simian kidney cells.
  Nucleic Acids Res, 34, 2305-2315.  
16615916 V.K.Batra, W.A.Beard, D.D.Shock, J.M.Krahn, L.C.Pedersen, and S.H.Wilson (2006).
Magnesium-induced assembly of a complete DNA polymerase catalytic complex.
  Structure, 14, 757-766.
PDB codes: 2fmp 2fmq 2fms
15743815 K.D.Carlson, and M.T.Washington (2005).
Mechanism of efficient and accurate nucleotide incorporation opposite 7,8-dihydro-8-oxoguanine by Saccharomyces cerevisiae DNA polymerase eta.
  Mol Cell Biol, 25, 2169-2176.  
16271888 L.G.Brieba, R.J.Kokoska, K.Bebenek, T.A.Kunkel, and T.Ellenberger (2005).
A lysine residue in the fingers subdomain of T7 DNA polymerase modulates the miscoding potential of 8-oxo-7,8-dihydroguanosine.
  Structure, 13, 1653-1659.
PDB code: 1zyq
15778433 N.Oka, and M.M.Greenberg (2005).
The effect of the 2-amino group of 7,8-dihydro-8-oxo-2'-deoxyguanosine on translesion synthesis and duplex stability.
  Nucleic Acids Res, 33, 1637-1643.  
15952890 S.Prakash, R.E.Johnson, and L.Prakash (2005).
Eukaryotic translesion synthesis DNA polymerases: specificity of structure and function.
  Annu Rev Biochem, 74, 317-353.  
16084394 V.K.Batra, W.A.Beard, D.D.Shock, L.C.Pedersen, and S.H.Wilson (2005).
Nucleotide-induced DNA polymerase active site motions accommodating a mutagenic DNA intermediate.
  Structure, 13, 1225-1233.
PDB codes: 1zjm 1zjn
16271879 W.A.Beard, and S.H.Wilson (2005).
Syn-full behavior by T7 DNA polymerase.
  Structure, 13, 1580-1582.  
15057282 E.Freisinger, A.P.Grollman, H.Miller, and C.Kisker (2004).
Lesion (in)tolerance reveals insights into DNA replication fidelity.
  EMBO J, 23, 1494-1505.
PDB codes: 1q9x 1q9y
15322558 G.W.Hsu, M.Ober, T.Carell, and L.S.Beese (2004).
Error-prone replication of oxidatively damaged DNA by a high-fidelity DNA polymerase.
  Nature, 431, 217-221.
PDB codes: 1u45 1u47 1u48 1u49 1u4b
15297882 L.G.Brieba, B.F.Eichman, R.J.Kokoska, S.Doublié, T.A.Kunkel, and T.Ellenberger (2004).
Structural basis for the dual coding potential of 8-oxoguanosine by a high-fidelity DNA polymerase.
  EMBO J, 23, 3452-3461.
PDB codes: 1t8e 1tk0 1tk5 1tk8 1tkd
15057283 M.Hogg, S.S.Wallace, and S.Doublié (2004).
Crystallographic snapshots of a replicative DNA polymerase encountering an abasic site.
  EMBO J, 23, 1483-1493.
PDB code: 2p5o
14988392 T.A.Kunkel (2004).
DNA replication fidelity.
  J Biol Chem, 279, 16895-16898.  
12517331 L.G.Brieba, and T.Ellenberger (2003).
Hold tight (but not too tight) to get it right: accurate bypass of an 8-oxoguanine lesion by DNA polymerase beta.
  Structure, 11, 1-2.  
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.

 

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