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PDBsum entry 1x9n

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protein dna_rna ligands links
Ligase/DNA PDB id
1x9n
Jmol
Contents
Protein chain
632 a.a. *
DNA/RNA
Ligands
AMP
* Residue conservation analysis
PDB id:
1x9n
Name: Ligase/DNA
Title: Crystal structure of human DNA ligase i bound to 5'-adenylat DNA
Structure: Dideoxy terminated DNA. Chain: b. Engineered: yes. 5'-phosphorylated DNA. Chain: c. Engineered: yes. Template DNA. Chain: d. Engineered: yes.
Source: Synthetic: yes. Homo sapiens. Human. Organism_taxid: 9606. Gene: lig1. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Tetramer (from PQS)
Resolution:
3.00Å     R-factor:   0.236     R-free:   0.268
Authors: J.M.Pascal,P.J.O'Brien,A.E.Tomkinson,T.Ellenberger
Key ref:
J.M.Pascal et al. (2004). Human DNA ligase I completely encircles and partially unwinds nicked DNA. Nature, 432, 473-478. PubMed id: 15565146 DOI: 10.1038/nature03082
Date:
23-Aug-04     Release date:   30-Nov-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P18858  (DNLI1_HUMAN) -  DNA ligase 1
Seq:
Struc:
 
Seq:
Struc:
919 a.a.
632 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.6.5.1.1  - Dna ligase (ATP).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + (deoxyribonucleotide)(n) + (deoxyribonucleotide)(m) = AMP + diphosphate + (deoxyribonucleotide)(n+m)
ATP
+ (deoxyribonucleotide)(n)
+ (deoxyribonucleotide)(m)
=
AMP
Bound ligand (Het Group name = AMP)
corresponds exactly
+ diphosphate
+ (deoxyribonucleotide)(n+m)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     DNA biosynthetic process   4 terms 
  Biochemical function     DNA binding     4 terms  

 

 
    reference    
 
 
DOI no: 10.1038/nature03082 Nature 432:473-478 (2004)
PubMed id: 15565146  
 
 
Human DNA ligase I completely encircles and partially unwinds nicked DNA.
J.M.Pascal, P.J.O'Brien, A.E.Tomkinson, T.Ellenberger.
 
  ABSTRACT  
 
The end-joining reaction catalysed by DNA ligases is required by all organisms and serves as the ultimate step of DNA replication, repair and recombination processes. One of three well characterized mammalian DNA ligases, DNA ligase I, joins Okazaki fragments during DNA replication. Here we report the crystal structure of human DNA ligase I (residues 233 to 919) in complex with a nicked, 5' adenylated DNA intermediate. The structure shows that the enzyme redirects the path of the double helix to expose the nick termini for the strand-joining reaction. It also reveals a unique feature of mammalian ligases: a DNA-binding domain that allows ligase I to encircle its DNA substrate, stabilizes the DNA in a distorted structure, and positions the catalytic core on the nick. Similarities in the toroidal shape and dimensions of DNA ligase I and the proliferating cell nuclear antigen sliding clamp are suggestive of an extensive protein-protein interface that may coordinate the joining of Okazaki fragments.
 
  Selected figure(s)  
 
Figure 2.
Figure 2: Lig1 intimately engages its DNA substrate. a, Stereo view of the Lig1 -DNA complex. Three domains of Lig1 (coloured as in Fig. 1b) fully encompass the AppDNA reaction intermediate. The DNA strands are coloured as in Fig. 1a, and the AppDNA linkage is drawn in blue. A poorly ordered surface loop (residues 385 to 392) was not modelled (grey spheres). b, Molecular surface of Lig1. The AdD is semi-transparent to highlight the AMP cofactor held within the AdD active site. c, The AMP cofactor anchors the 5' P of the downstream DNA strand for interactions with catalytic residues. Two peaks of electron density from an F[o] - F[c] difference map (purple) mark the locations of two potential metal-binding sites.
Figure 5.
Figure 5: Two active conformations of the OBD. a, Lig1 is modelled in a conformation competent for step 1 by superimposing the OBD (yellow) from Lig1 onto that of the mRNA capping enzyme^21 (PDB code 1CKM). The surface of the OBD bearing motif VI residues (VI; pink) faces the AdD (green) active site. The DBD (red) must pivot 20 to accommodate this conformation. b, OBD residues 871 and 872 (blue) face the active site during steps 2 and 3 (Lig1 -DNA complex). In this conformation, motif VI residues are far from the active site. The relative positioning of the C-terminal -helix (cyan) highlights the rotation/movement of the OBD between these alternate conformations (compare a and b).
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2004, 432, 473-478) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21278448 L.Zheng, and B.Shen (2011).
Okazaki fragment maturation: nucleases take centre stage.
  J Mol Cell Biol, 3, 23-30.  
20929870 L.Zheng, J.Jia, L.D.Finger, Z.Guo, C.Zer, and B.Shen (2011).
Functional regulation of FEN1 nuclease and its link to cancer.
  Nucleic Acids Res, 39, 781-794.  
21984210 P.Tumbale, C.D.Appel, R.Kraehenbuehl, P.D.Robertson, J.S.Williams, J.Krahn, I.Ahel, and R.S.Williams (2011).
Structure of an aprataxin-DNA complex with insights into AOA1 neurodegenerative disease.
  Nat Struct Mol Biol, 18, 1189-1195.
PDB code: 3szq
21496641 S.E.Tsutakawa, S.Classen, B.R.Chapados, A.S.Arvai, L.D.Finger, G.Guenther, C.G.Tomlinson, P.Thompson, A.H.Sarker, B.Shen, P.K.Cooper, J.A.Grasby, and J.A.Tainer (2011).
Human flap endonuclease structures, DNA double-base flipping, and a unified understanding of the FEN1 superfamily.
  Cell, 145, 198-211.
PDB codes: 3q8k 3q8l 3q8m
21265749 T.R.Beattie, and S.D.Bell (2011).
The role of the DNA sliding clamp in Okazaki fragment maturation in archaea and eukaryotes.
  Biochem Soc Trans, 39, 70-76.  
20097903 A.Doi, S.P.Pack, and K.Makino (2010).
Comparison of the molecular influences of NO-induced lesions in DNA strands on the reactivity of polynucleotide kinases, DNA ligases and DNA polymerases.
  J Biochem, 147, 697-703.  
19913033 A.Piserchio, P.A.Nair, S.Shuman, and R.Ghose (2010).
Solution NMR studies of Chlorella virus DNA ligase-adenylate.
  J Mol Biol, 395, 291-308.  
20098496 J.D.Durrant, R.E.Amaro, L.Xie, M.D.Urbaniak, M.A.Ferguson, A.Haapalainen, Z.Chen, A.M.Di Guilmi, F.Wunder, P.E.Bourne, and J.A.McCammon (2010).
A multidimensional strategy to detect polypharmacological targets in the absence of structural and sequence homology.
  PLoS Comput Biol, 6, e1000648.  
19965771 L.J.Eccles, M.E.Lomax, and P.O'Neill (2010).
Hierarchy of lesion processing governs the repair, double-strand break formation and mutability of three-lesion clustered DNA damage.
  Nucleic Acids Res, 38, 1123-1134.  
20515430 R.L.Flynn, and L.Zou (2010).
Oligonucleotide/oligosaccharide-binding fold proteins: a growing family of genome guardians.
  Crit Rev Biochem Mol Biol, 45, 266-275.  
  21129204 T.C.Mueser, J.M.Hinerman, J.M.Devos, R.A.Boyer, and K.J.Williams (2010).
Structural analysis of bacteriophage T4 DNA replication: a review in the Virology Journal series on bacteriophage T4 and its relatives.
  Virol J, 7, 359.  
  20862368 T.Ochi, B.L.Sibanda, Q.Wu, D.Y.Chirgadze, V.M.Bolanos-Garcia, and T.L.Blundell (2010).
Structural biology of DNA repair: spatial organisation of the multicomponent complexes of nonhomologous end joining.
  J Nucleic Acids, 2010, 0.  
19101707 E.Fanning, and K.Zhao (2009).
SV40 DNA replication: from the A gene to a nanomachine.
  Virology, 384, 352-359.  
  19342782 E.Y.Bezsudnova, M.V.Kovalchuk, A.V.Mardanov, K.M.Poliakov, V.O.Popov, N.V.Ravin, K.G.Skryabin, V.A.Smagin, T.N.Stekhanova, and T.V.Tikhonova (2009).
Overexpression, purification and crystallization of a thermostable DNA ligase from the archaeon Thermococcus sp. 1519.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 65, 368-371.  
19881914 F.J.López de Saro (2009).
Regulation of interactions with sliding clamps during DNA replication and repair.
  Curr Genomics, 10, 206-215.  
19596905 K.K.Karanja, and D.M.Livingston (2009).
C-terminal flap endonuclease (rad27) mutations: lethal interactions with a DNA ligase I mutation (cdc9-p) and suppression by proliferating cell nuclear antigen (POL30) in Saccharomyces cerevisiae.
  Genetics, 183, 63-78.  
19255439 K.Mayanagi, S.Kiyonari, M.Saito, T.Shirai, Y.Ishino, and K.Morikawa (2009).
Mechanism of replication machinery assembly as revealed by the DNA ligase-PCNA-DNA complex architecture.
  Proc Natl Acad Sci U S A, 106, 4647-4652.  
19690099 N.Tanaka, and S.Shuman (2009).
Structure-activity relationships in human RNA 3'-phosphate cyclase.
  RNA, 15, 1865-1874.  
20354588 R.V.Swift, and R.E.Amaro (2009).
Discovery and design of DNA and RNA ligase inhibitors in infectious microorganisms.
  Expert Opin Drug Discov, 4, 1281-1294.  
19329793 S.Shuman (2009).
DNA ligases: progress and prospects.
  J Biol Chem, 284, 17365-17369.  
19523882 W.Song, J.M.Pascal, T.Ellenberger, and A.E.Tomkinson (2009).
The DNA binding domain of human DNA ligase I interacts with both nicked DNA and the DNA sliding clamps, PCNA and hRad9-hRad1-hHus1.
  DNA Repair (Amst), 8, 912-919.  
19589734 X.Chen, J.D.Ballin, J.Della-Maria, M.S.Tsai, E.J.White, A.E.Tomkinson, and G.M.Wilson (2009).
Distinct kinetics of human DNA ligases I, IIIalpha, IIIbeta, and IV reveal direct DNA sensing ability and differential physiological functions in DNA repair.
  DNA Repair (Amst), 8, 961-968.  
18458338 A.Crut, P.A.Nair, D.A.Koster, S.Shuman, and N.H.Dekker (2008).
Dynamics of phosphodiester synthesis by DNA ligase.
  Proc Natl Acad Sci U S A, 105, 6894-6899.  
18238776 E.Cotner-Gohara, I.K.Kim, A.E.Tomkinson, and T.Ellenberger (2008).
Two DNA-binding and nick recognition modules in human DNA ligase III.
  J Biol Chem, 283, 10764-10772.  
18203718 H.Zhu, and S.Shuman (2008).
Bacterial nonhomologous end joining ligases preferentially seal breaks with a 3'-OH monoribonucleotide.
  J Biol Chem, 283, 8331-8339.  
18262407 J.M.Pascal (2008).
DNA and RNA ligases: structural variations and shared mechanisms.
  Curr Opin Struct Biol, 18, 96.  
18511537 M.A.Brooks, L.Meslet-Cladiére, M.Graille, J.Kuhn, K.Blondeau, H.Myllykallio, and H.van Tilbeurgh (2008).
The structure of an archaeal homodimeric ligase which has RNA circularization activity.
  Protein Sci, 17, 1336-1345.
PDB code: 2vug
18080330 N.Dwivedi, D.Dube, J.Pandey, B.Singh, V.Kukshal, R.Ramachandran, and R.P.Tripathi (2008).
NAD(+)-dependent DNA ligase: a novel target waiting for the right inhibitor.
  Med Res Rev, 28, 545-568.  
18981420 R.E.Amaro, A.Schnaufer, H.Interthal, W.Hol, K.D.Stuart, and J.A.McCammon (2008).
Discovery of drug-like inhibitors of an essential RNA-editing ligase in Trypanosoma brucei.
  Proc Natl Acad Sci U S A, 105, 17278-17283.  
18630893 S.Zhong, X.Chen, X.Zhu, B.Dziegielewska, K.E.Bachman, T.Ellenberger, J.D.Ballin, G.M.Wilson, A.E.Tomkinson, and A.D.MacKerell (2008).
Identification and validation of human DNA ligase inhibitors using computer-aided drug design.
  J Med Chem, 51, 4553-4562.  
18518823 T.Ellenberger, and A.E.Tomkinson (2008).
Eukaryotic DNA ligases: structural and functional insights.
  Annu Rev Biochem, 77, 313-338.  
18795946 T.I.Meier, D.Yan, R.B.Peery, K.A.McAllister, C.Zook, S.B.Peng, and G.Zhao (2008).
Identification and characterization of an inhibitor specific to bacterial NAD+-dependent DNA ligases.
  FEBS J, 275, 5258-5271.  
18451142 X.Chen, S.Zhong, X.Zhu, B.Dziegielewska, T.Ellenberger, G.M.Wilson, A.D.MacKerell, and A.E.Tomkinson (2008).
Rational design of human DNA ligase inhibitors that target cellular DNA replication and repair.
  Cancer Res, 68, 3169-3177.  
17923696 A.Prasad, S.S.Wallace, and D.S.Pederson (2007).
Initiation of base excision repair of oxidative lesions in nucleosomes by the human, bifunctional DNA glycosylase NTH1.
  Mol Cell Biol, 27, 8442-8453.  
17136487 B.R.Jackson, C.Noble, M.Lavesa-Curto, P.L.Bond, and R.P.Bowater (2007).
Characterization of an ATP-dependent DNA ligase from the acidophilic archaeon "Ferroplasma acidarmanus" Fer1.
  Extremophiles, 11, 315-327.  
18078545 C.D.Putnam, M.Hammel, G.L.Hura, and J.A.Tainer (2007).
X-ray solution scattering (SAXS) combined with crystallography and computation: defining accurate macromolecular structures, conformations and assemblies in solution.
  Q Rev Biophys, 40, 191-285.  
17512402 G.L.Moldovan, B.Pfander, and S.Jentsch (2007).
PCNA, the maestro of the replication fork.
  Cell, 129, 665-679.  
17488851 H.Zhu, and S.Shuman (2007).
Characterization of Agrobacterium tumefaciens DNA ligases C and D.
  Nucleic Acids Res, 35, 3631-3645.  
17296606 I.Muylaert, and P.Elias (2007).
Knockdown of DNA ligase IV/XRCC4 by RNA interference inhibits herpes simplex virus type I DNA replication.
  J Biol Chem, 282, 10865-10872.  
17466627 J.Nandakumar, P.A.Nair, and S.Shuman (2007).
Last stop on the road to repair: structure of E. coli DNA ligase bound to nicked DNA-adenylate.
  Mol Cell, 26, 257-271.
PDB code: 2owo
17688957 J.S.Buguliskis, L.J.Casta, C.E.Butz, Y.Matsumoto, and T.F.Taraschi (2007).
Expression and biochemical characterization of Plasmodium falciparum DNA ligase I.
  Mol Biochem Parasitol, 155, 128-137.  
17283043 L.Zheng, H.Dai, J.Qiu, Q.Huang, and B.Shen (2007).
Disruption of the FEN-1/PCNA interaction results in DNA replication defects, pulmonary hypoplasia, pancytopenia, and newborn lethality in mice.
  Mol Cell Biol, 27, 3176-3186.  
17618295 P.A.Nair, J.Nandakumar, P.Smith, M.Odell, C.D.Lima, and S.Shuman (2007).
Structural basis for nick recognition by a minimal pluripotent DNA ligase.
  Nat Struct Mol Biol, 14, 770-778.
PDB codes: 2q2t 2q2u
17487442 S.Kiyonari, T.Kamigochi, and Y.Ishino (2007).
A single amino acid substitution in the DNA-binding domain of Aeropyrum pernix DNA ligase impairs its interaction with proliferating cell nuclear antigen.
  Extremophiles, 11, 675-684.  
17938628 S.Shuman, and M.S.Glickman (2007).
Bacterial DNA repair by non-homologous end joining.
  Nat Rev Microbiol, 5, 852-861.  
17308348 S.Vijayakumar, B.R.Chapados, K.H.Schmidt, R.D.Kolodner, J.A.Tainer, and A.E.Tomkinson (2007).
The C-terminal domain of yeast PCNA is required for physical and functional interactions with Cdc9 DNA ligase.
  Nucleic Acids Res, 35, 1624-1637.
PDB code: 2od8
17561505 W.Song, D.S.Levin, J.Varkey, S.Post, V.P.Bermudez, J.Hurwitz, and A.E.Tomkinson (2007).
A conserved physical and functional interaction between the cell cycle checkpoint clamp loader and DNA ligase I of eukaryotes.
  J Biol Chem, 282, 22721-22730.  
17323928 X.Zhao, J.G.Muller, M.Halasyam, S.S.David, and C.J.Burrows (2007).
In vitro ligation of oligodeoxynucleotides containing C8-oxidized purine lesions using bacteriophage T4 DNA ligase.
  Biochemistry, 46, 3734-3744.  
16420348 A.Zhao, F.C.Gray, and S.A.MacNeill (2006).
ATP- and NAD+-dependent DNA ligases share an essential function in the halophilic archaeon Haloferax volcanii.
  Mol Microbiol, 59, 743-752.  
16476729 D.Akey, A.Martins, J.Aniukwu, M.S.Glickman, S.Shuman, and J.M.Berger (2006).
Crystal structure and nonhomologous end-joining function of the ligase component of Mycobacterium DNA ligase D.
  J Biol Chem, 281, 13412-13423.
PDB code: 1vs0
17158702 E.R.Barry, and S.D.Bell (2006).
DNA replication in the archaea.
  Microbiol Mol Biol Rev, 70, 876-887.  
17052461 J.M.Pascal, O.V.Tsodikov, G.L.Hura, W.Song, E.A.Cotner, S.Classen, A.E.Tomkinson, J.A.Tainer, and T.Ellenberger (2006).
A flexible interface between DNA ligase and PCNA supports conformational switching and efficient ligation of DNA.
  Mol Cell, 24, 279-291.
PDB codes: 2hii 2hik 2hiv 2hix
17082787 J.M.Pascal, and T.Ellenberger (2006).
RNA ligase does the AMP shuffle.
  Nat Struct Mol Biol, 13, 950-951.  
17068206 L.K.Wang, B.Schwer, and S.Shuman (2006).
Structure-guided mutational analysis of T4 RNA ligase 1.
  RNA, 12, 2126-2134.  
16829513 S.Kiyonari, K.Takayama, H.Nishida, and Y.Ishino (2006).
Identification of a novel binding motif in Pyrococcus furiosus DNA ligase for the functional interaction with proliferating cell nuclear antigen.
  J Biol Chem, 281, 28023-28032.  
16731526 W.Wang, L.A.Lindsey-Boltz, A.Sancar, and R.A.Bambara (2006).
Mechanism of stimulation of human DNA ligase I by the Rad9-rad1-Hus1 checkpoint complex.
  J Biol Chem, 281, 20865-20872.  
16079237 E.W.Refsland, and D.M.Livingston (2005).
Interactions among DNA ligase I, the flap endonuclease and proliferating cell nuclear antigen in the expansion and contraction of CAG repeat tracts in yeast.
  Genetics, 171, 923-934.  
16285867 J.M.Daley, P.L.Palmbos, D.Wu, and T.E.Wilson (2005).
Nonhomologous end joining in yeast.
  Annu Rev Genet, 39, 431-451.  
15851476 J.Nandakumar, and S.Shuman (2005).
Dual mechanisms whereby a broken RNA end assists the catalysis of its repair by T4 RNA ligase 2.
  J Biol Chem, 280, 23484-23489.  
15965249 J.Subramanian, S.Vijayakumar, A.E.Tomkinson, and N.Arnheim (2005).
Genetic instability induced by overexpression of DNA ligase I in budding yeast.
  Genetics, 171, 427-441.  
15923379 L.K.Wang, and S.Shuman (2005).
Structure-function analysis of yeast tRNA ligase.
  RNA, 11, 966-975.  
16199559 N.Keppetipola, and S.Shuman (2005).
Characterization of a thermophilic ATP-dependent DNA ligase from the euryarchaeon Pyrococcus horikoshii.
  J Bacteriol, 187, 6902-6908.  
16361267 S.K.Srivastava, D.Dube, N.Tewari, N.Dwivedi, R.P.Tripathi, and R.Ramachandran (2005).
Mycobacterium tuberculosis NAD+-dependent DNA ligase is selectively inhibited by glycosylamines compared with human DNA ligase I.
  Nucleic Acids Res, 33, 7090-7101.  
15901723 S.K.Srivastava, R.P.Tripathi, and R.Ramachandran (2005).
NAD+-dependent DNA Ligase (Rv3014c) from Mycobacterium tuberculosis. Crystal structure of the adenylation domain and identification of novel inhibitors.
  J Biol Chem, 280, 30273-30281.
PDB code: 1zau
15805117 S.N.Naryzhny, H.Zhao, and H.Lee (2005).
Proliferating cell nuclear antigen (PCNA) may function as a double homotrimer complex in the mammalian cell.
  J Biol Chem, 280, 13888-13894.  
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 code is shown on the right.