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DNA repair PDB id
1ea6
Jmol
Contents
Protein chains
304 a.a. *
Ligands
ADP ×2
Metals
_MG ×2
Waters ×50
* Residue conservation analysis
PDB id:
1ea6
Name: DNA repair
Title: N-terminal 40kda fragment of nhpms2 complexed with adp
Structure: Pms1 protein homolog 2. Chain: a, b. Fragment: n-terminal 40kda, residues 1-364. Synonym: hpms2, DNA mismatch repair protein pms2. Engineered: yes. Other_details: nhpms2 complexed with adp
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.7Å     R-factor:   0.230     R-free:   0.262
Authors: A.Guarne,M.S.Junop,W.Yang
Key ref:
A.Guarné et al. (2001). Structure and function of the N-terminal 40 kDa fragment of human PMS2: a monomeric GHL ATPase. EMBO J, 20, 5521-5531. PubMed id: 11574484 DOI: 10.1093/emboj/20.19.5521
Date:
10-Jul-01     Release date:   23-Nov-01    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P54278  (PMS2_HUMAN) -  Mismatch repair endonuclease PMS2
Seq:
Struc: 		 
Seq:
Struc: 		862 a.a.
304 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     mismatch repair   1 term 
  Biochemical function     ATP binding     2 terms  

 

 
DOI no: 10.1093/emboj/20.19.5521 EMBO J 20:5521-5531 (2001)
PubMed id: 11574484  
 
 
Structure and function of the N-terminal 40 kDa fragment of human PMS2: a monomeric GHL ATPase.
A.Guarné, M.S.Junop, W.Yang.
 
  ABSTRACT  
 
Human MutLalpha, a heterodimer of hMLH1 and hPMS2, is essential for DNA mismatch repair. Inactivation of the hmlh1 or hpms2 genes by mutation or epigenesis causes genomic instability and a predisposition to hereditary non-polyposis cancer. We report here the X-ray crystal structures of the conserved N-terminal 40 kDa fragment of hPMS2, NhPMS2, and its complexes with ATPgammaS and ADP at 1.95, 2.7 and 2.7 A resolution, respectively. The NhPMS2 structures closely resemble the ATPase fragment of Escherichia coli MutL, which coordinates protein-protein interactions in mismatch repair by undergoing structural transformation upon binding of ATP. Unlike the E.coli MutL, whose ATPase activity requires protein dimerization, the monomeric form of NhPMS2 is active both in ATP hydrolysis and DNA binding. NhPMS2 is the first example of a GHL ATPase active as a monomer, suggesting that its activity may be modulated by hMLH1 in MutLalpha, and vice versa. The potential heterodimer interface revealed by crystallography provides a mutagenesis target for functional studies of MutLalpha.
 
  Selected figure(s)  
 
Figure 2.
Figure 2 Structure of NhPMS2. (A and B) Orthogonal views of NhPMS2 structure in ribbon diagram. -strands are shown as purple arrows, and 3[10] helices as gold ribbons and connecting loops as light green coils. Disordered loops are shown as green dotted lines. Secondary structures are labeled using the same convention as for the LN40 structure. New structural elements in NhPMS2 are labeled with the same name as the following structural element with a prime (E' helix lies between D and E helices). N- and C-termini are marked for clarity. (C) Sequence alignment of hPMS2, hMLH1 and MutL. Loops undergoing structural transformation in LN40 are labeled and shown in orange. ATP binding motifs (I -IV) are boxed in blue. The residues conserved in the GHL superfamily are shaded in blue, the rest of the conserved residues are shaded in light yellow. 		Figure 4.
Figure 4 Comparison of the active site of LN40 and NhPMS2. (A) Ribbon diagram of the constant part of the ATP binding site. Superimposition of NhPMS2 (gold), LN40 -ADPnP (green) and apo-LN40 (blue) encompassing motifs I, II and IV, and helices B and D is shown in stereo. (B -E) Ribbon diagrams of the complete ATP binding site of apo-LN40 (B), LN40 complexed with ADPnP (C), apo-NhPMS2 (D), and NhPMS2 complexed with ATP S (E). The ATP lids are shown in solid magenta when traceable. The start and end residues of the ATP lid of NhPMS2 structures are labeled and marked with red and blue arrowheads, respectively. Side chains of conserved residues involved in nucleotide binding are shown as ball-and-sticks. Arg95 of LN40 and its equivalent, Arg107 of hPMS2, are shown as magenta ball-and-sticks. The bound nucleotide is shown as a gray stick model.
 
  The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: EMBO J (2001, 20, 5521-5531) copyright 2001.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21064154 A.Brieger, R.Adam, S.Passmann, G.Plotz, S.Zeuzem, and J.Trojan (2011).
A CRM1-dependent nuclear export pathway is involved in the regulation of MutLα subcellular localization.
  Genes Chromosomes Cancer, 50, 59-70.  
21354867 A.N.Schorzman, L.Perera, J.M.Cutalo-Patterson, L.C.Pedersen, L.G.Pedersen, T.A.Kunkel, and K.B.Tomer (2011).
Modeling of the DNA-binding site of yeast Pms1 by mass spectrometry.
  DNA Repair (Amst), 10, 454-465.  
20571910 C.Galles, R.L.Gomez, and C.P.Spampinato (2011).
PMS1 from Arabidopsis thaliana: optimization of protein overexpression in Escherichia coli.
  Mol Biol Rep, 38, 1063-1070.  
20961292 H.Iino, K.Kim, A.Shimada, R.Masui, S.Kuramitsu, and K.Fukui (2011).
Characterization of C- and N-terminal domains of Aquifex aeolicus MutL endonuclease: N-terminal domain stimulates the endonuclease activity of C-terminal domain in a zinc-dependent manner.
  Biosci Rep, 31, 309-322.  
20657586 J.Gorman, A.J.Plys, M.L.Visnapuu, E.Alani, and E.C.Greene (2010).
Visualizing one-dimensional diffusion of eukaryotic DNA repair factors along a chromatin lattice.
  Nat Struct Mol Biol, 17, 932-938.  
  20725617 K.Fukui (2010).
DNA mismatch repair in eukaryotes and bacteria.
  J Nucleic Acids, 2010, 0.  
20603082 M.C.Pillon, J.J.Lorenowicz, M.Uckelmann, A.D.Klocko, R.R.Mitchell, Y.S.Chung, P.Modrich, G.C.Walker, L.A.Simmons, P.Friedhoff, and A.Guarné (2010).
Structure of the endonuclease domain of MutL: unlicensed to cut.
  Mol Cell, 39, 145-151.
PDB codes: 3gab 3kdg 3kdk
20138591 M.E.Arana, S.F.Holmes, J.M.Fortune, A.F.Moon, L.C.Pedersen, and T.A.Kunkel (2010).
Functional residues on the surface of the N-terminal domain of yeast Pms1.
  DNA Repair (Amst), 9, 448-457.
PDB code: 3h4l
21171995 S.Jaeger, C.T.Sers, and U.Leser (2010).
Combining modularity, conservation, and interactions of proteins significantly increases precision and coverage of protein function prediction.
  BMC Genomics, 11, 717.  
19148896 V.Leong, J.Lorenowicz, N.Kozij, and A.Guarné (2009).
Nuclear import of human MLH1, PMS2, and MutLalpha: redundancy is the key.
  Mol Carcinog, 48, 742-750.  
19039682 W.Sjursen, I.Bjørnevoll, L.F.Engebretsen, K.Fjelland, T.Halvorsen, and H.E.Myrvold (2009).
A homozygote splice site PMS2 mutation as cause of Turcot syndrome gives rise to two different abnormal transcripts.
  Fam Cancer, 8, 179-186.  
18206974 E.J.Sacho, F.A.Kadyrov, P.Modrich, T.A.Kunkel, and D.A.Erie (2008).
Direct visualization of asymmetric adenine-nucleotide-induced conformational changes in MutL alpha.
  Mol Cell, 29, 112-121.  
18768816 I.Marinovic-Terzic, A.Yoshioka-Yamashita, H.Shimodaira, E.Avdievich, I.C.Hunton, R.D.Kolodner, W.Edelmann, and J.Y.Wang (2008).
Apoptotic function of human PMS2 compromised by the nonsynonymous single-nucleotide polymorphic variant R20Q.
  Proc Natl Acad Sci U S A, 105, 13993-13998.  
18310077 K.Fukui, M.Nishida, N.Nakagawa, R.Masui, and S.Kuramitsu (2008).
Bound nucleotide controls the endonuclease activity of mismatch repair enzyme MutL.
  J Biol Chem, 283, 12136-12145.  
18406444 P.Hsieh, and K.Yamane (2008).
DNA mismatch repair: molecular mechanism, cancer, and ageing.
  Mech Ageing Dev, 129, 391-407.  
17851451 S.Krüger, M.Kinzel, C.Walldorf, S.Gottschling, A.Bier, S.Tinschert, A.von Stackelberg, W.Henn, H.Görgens, S.Boue, K.Kölble, R.Büttner, and H.K.Schackert (2008).
Homozygous PMS2 germline mutations in two families with early-onset haematological malignancy, brain tumours, HNPCC-associated tumours, and signs of neurofibromatosis type 1.
  Eur J Hum Genet, 16, 62-72.  
16913423 D.G.Shpakovskii, E.K.Shematorova, and G.V.Shpakovskii (2006).
Human PMS2 gene family: origin, molecular evolution, and biological implications.
  Dokl Biochem Biophys, 408, 175-179.  
16546997 F.J.López de Saro, M.G.Marinus, P.Modrich, and M.O'Donnell (2006).
The beta sliding clamp binds to multiple sites within MutL and MutS.
  J Biol Chem, 281, 14340-14349.  
17135187 G.Plotz, C.Welsch, L.Giron-Monzon, P.Friedhoff, M.Albrecht, A.Piiper, R.M.Biondi, T.Lengauer, S.Zeuzem, and J.Raedle (2006).
Mutations in the MutSalpha interaction interface of MLH1 can abolish DNA mismatch repair.
  Nucleic Acids Res, 34, 6574-6586.  
16821093 G.Plotz, S.Zeuzem, and J.Raedle (2006).
DNA mismatch repair and Lynch syndrome.
  J Mol Histol, 37, 271-283.  
16619239 M.Clendenning, H.Hampel, J.LaJeunesse, A.Lindblom, J.Lockman, M.Nilbert, L.Senter, K.Sotamaa, and A.de la Chapelle (2006).
Long-range PCR facilitates the identification of PMS2-specific mutations.
  Hum Mutat, 27, 490-495.  
16623698 S.H.Jun, T.G.Kim, and C.Ban (2006).
DNA mismatch repair system. Classical and fresh roles.
  FEBS J, 273, 1609-1619.  
15952900 T.A.Kunkel, and D.A.Erie (2005).
DNA mismatch repair.
  Annu Rev Biochem, 74, 681-710.  
15184898 S.M.Lipkin, L.S.Rozek, G.Rennert, W.Yang, P.C.Chen, J.Hacia, N.Hunt, B.Shin, S.Fodor, M.Kokoris, J.K.Greenson, E.Fearon, H.Lynch, F.Collins, and S.B.Gruber (2004).
The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer.
  Nat Genet, 36, 694-699.  
12743174 C.E.Schrader, J.Vardo, and J.Stavnezer (2003).
Mlh1 can function in antibody class switch recombination independently of Msh2.
  J Exp Med, 197, 1377-1383.  
12820877 E.Antony, and M.M.Hingorani (2003).
Mismatch recognition-coupled stabilization of Msh2-Msh6 in an ATP-bound state at the initiation of DNA repair.
  Biochemistry, 42, 7682-7693.  
  12618391 E.R.Hoffmann, P.V.Shcherbakova, T.A.Kunkel, and R.H.Borts (2003).
MLH1 mutations differentially affect meiotic functions in Saccharomyces cerevisiae.
  Genetics, 163, 515-526.  
12682353 M.C.Hall, P.V.Shcherbakova, J.M.Fortune, C.H.Borchers, J.M.Dial, K.B.Tomer, and T.A.Kunkel (2003).
DNA binding by yeast Mlh1 and Pms1: implications for DNA mismatch repair.
  Nucleic Acids Res, 31, 2025-2034.  
14527292 M.J.Schofield, and P.Hsieh (2003).
DNA mismatch repair: molecular mechanisms and biological function.
  Annu Rev Microbiol, 57, 579-608.  
12783580 P.Chène (2003).
The ATPases: a new family for a family-based drug design approach.
  Expert Opin Ther Targets, 7, 453-461.  
11751892 B.A.Owen, W.P.Sullivan, S.J.Felts, and D.O.Toft (2002).
Regulation of heat shock protein 90 ATPase activity by sequences in the carboxyl terminus.
  J Biol Chem, 277, 7086-7091.  
  12454061 C.Welz-Voegele, J.E.Stone, P.T.Tran, H.M.Kearney, R.M.Liskay, T.D.Petes, and S.Jinks-Robertson (2002).
Alleles of the yeast Pms1 mismatch-repair gene that differentially affect recombination- and replication-related processes.
  Genetics, 162, 1131-1145.  
11897781 G.Tomer, A.B.Buermeyer, M.M.Nguyen, and R.M.Liskay (2002).
Contribution of human mlh1 and pms2 ATPase activities to DNA mismatch repair.
  J Biol Chem, 277, 21801-21809.  
11717305 M.C.Hall, P.V.Shcherbakova, and T.A.Kunkel (2002).
Differential ATP binding and intrinsic ATP hydrolysis by amino-terminal domains of the yeast Mlh1 and Pms1 proteins.
  J Biol Chem, 277, 3673-3679.  
11948175 M.Räschle, P.Dufner, G.Marra, and J.Jiricny (2002).
Mutations within the hMLH1 and hPMS2 subunits of the human MutLalpha mismatch repair factor affect its ATPase activity, but not its ability to interact with hMutSalpha.
  J Biol Chem, 277, 21810-21820.  
12209147 P.Chène (2002).
ATPases as drug targets: learning from their structure.
  Nat Rev Drug Discov, 1, 665-673.  
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.