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PDBsum entry 2o8e

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protein dna_rna ligands metals Protein-protein interface(s) links
DNA binding protein/DNA PDB id
2o8e
Jmol
Contents
Protein chains
824 a.a. *
935 a.a. *
DNA/RNA
Ligands
ADP
Metals
_MG
Waters ×10
* Residue conservation analysis
PDB id:
2o8e
Name: DNA binding protein/DNA
Title: Human mutsalpha (msh2/msh6) bound to a g t mispair, with adp msh2 only
Structure: 5'-d( Gp Ap Ap Cp Cp Gp Cp Gp Gp Gp Cp Tp Ap Gp G chain: e. Engineered: yes. Mutation: yes. 5'-d( Cp Cp Tp Ap Gp Cp Cp Tp Gp Cp Gp Gp Tp Tp C chain: f. Engineered: yes. DNA mismatch repair protein msh2. Chain: a.
Source: Synthetic: yes. Homo sapiens. Human. Organism_taxid: 9606. Gene: msh2. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Gene: msh6, gtbp.
Resolution:
3.30Å     R-factor:   0.255     R-free:   0.291
Authors: J.J.Warren,T.J.Pohlhaus,A.Changela,P.L.Modrich,L.S.Beese
Key ref:
J.J.Warren et al. (2007). Structure of the Human MutSalpha DNA Lesion Recognition Complex. Mol Cell, 26, 579-592. PubMed id: 17531815 DOI: 10.1016/j.molcel.2007.04.018
Date:
12-Dec-06     Release date:   05-Jun-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P43246  (MSH2_HUMAN) -  DNA mismatch repair protein Msh2
Seq:
Struc:
 
Seq:
Struc:
934 a.a.
824 a.a.*
Protein chain
Pfam   ArchSchema ?
P52701  (MSH6_HUMAN) -  DNA mismatch repair protein Msh6
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1360 a.a.
935 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   5 terms 
  Biological process     response to DNA damage stimulus   30 terms 
  Biochemical function     nucleotide binding     28 terms  

 

 
DOI no: 10.1016/j.molcel.2007.04.018 Mol Cell 26:579-592 (2007)
PubMed id: 17531815  
 
 
Structure of the Human MutSalpha DNA Lesion Recognition Complex.
J.J.Warren, T.J.Pohlhaus, A.Changela, R.R.Iyer, P.L.Modrich, L.S.Beese.
 
  ABSTRACT  
 
Mismatch repair (MMR) ensures the fidelity of DNA replication, initiates the cellular response to certain classes of DNA damage, and has been implicated in the generation of immune diversity. Each of these functions depends on MutSalpha (MSH2*MSH6 heterodimer). Inactivation of this protein complex is responsible for tumor development in about half of known hereditary nonpolyposis colorectal cancer kindreds and also occurs in sporadic tumors in a variety of tissues. Here, we describe a series of crystal structures of human MutSalpha bound to different DNA substrates, each known to elicit one of the diverse biological responses of the MMR pathway. All lesions are recognized in a similar manner, indicating that diversity of MutSalpha-dependent responses to DNA lesions is generated in events downstream of this lesion recognition step. This study also allows rigorous mapping of cancer-causing mutations and furthermore suggests structural pathways for allosteric communication between different regions within the heterodimer.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Overview of the Structure of Human MutSα
(A) Ribbon diagram of the structure of a MutSα/ADP/G•T mispair complex. Blue, MSH6; red, MSH2; green ribbon, DNA; yellow, ADP; and green spheres, Mg^2+ ions. Positions of the ABC ATPase domains and the two channels in MutSα are indicated. Long α helices connecting clamp and ATPase domains in MSH2 and MSH6 are colored orange and cyan, respectively.
(B) Orthogonal, expanded view of the DNA binding domains of MutSα. DNA is shown as sticks, colored by atom type, with the central G•T mispair colored yellow.
(C) Expanded view of the upper channel in MutSα, colored as in (A) and shown as ribbons and a transparent surface. Disordered loops are shown as dashed lines with residue numbers.
(D) The domain structure of MSH6. Center: domains 1–5 are colored blue, green, yellow, orange, and red, respectively. Periphery: exploded view of each domain, labeled and colored with blue-red “chainbows” from the N- to C termini of the domain. Figures were generated with PyMOL (DeLano, 2002).
Figure 5.
Figure 5. Common Binding Mode for MutSα Substrates
(A) Interactions between a G•T mispair and an adjacent base pair with MSH6 domain 1 (shown as sticks under a semitransparent electrostatic surface).
(B) Protein-mispair contacts in a MutSα/G•dU/DNA complex. Putative hydrogen bonds are shown as dashed lines. Interacting residues (defined with LIGPLOT [Wallace et al., 1995]) are labeled. Orientation is rotated vert, similar 90° from (A).
(C) Protein mispair contacts in a MutSα/O^6-methyl-guanine/DNA complex, colored, labeled, and oriented as in (B).
(D) Interactions between a single base T insert substrate (cyan carbons) or a G•T mispair (green carbons) substrate and MSH6 domain 1 (blue surface). Hydrogen bonds are shown as dashed lines. Orientation is approximately the same as (A).
(E) Protein-DNA interactions in the MutSα-DNA complex. Amino acids that make hydrogen bonding (red lines) or van der Waals interactions (gray lines) are indicated with blue text (MSH6) or red text (MSH2). Dashed lines group the amino acids by protein domain as indicated. Interactions were classified by using Probe (Word et al., 1999).
(F) Structures with G•T (red), T insert (green) were superimposed on domain 1 of MSH6. DNAs from both complexes are shown as sticks, and backbone traces of MSH2 are shown as ribbons and surfaces. The arrow indicates the movement of domains 4 and 3 of MSH2 in the insert structure that compensates for the slight change in the DNA substrate register.
 
  The above figures are reprinted by permission from Cell Press: Mol Cell (2007, 26, 579-592) copyright 2007.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
22179786 S.Gupta, M.Gellert, and W.Yang (2012).
Mechanism of mismatch recognition revealed by human MutSβ bound to unpaired DNA loops.
  Nat Struct Mol Biol, 19, 72-78.
PDB codes: 3thw 3thx 3thy 3thz
21278758 C.Jeong, W.K.Cho, K.M.Song, C.Cook, T.Y.Yoon, C.Ban, R.Fishel, and J.B.Lee (2011).
MutS switches between two fundamentally distinct clamps during mismatch repair.
  Nat Struct Mol Biol, 18, 379-385.  
21282622 L.Y.Kadyrova, E.R.Blanko, and F.A.Kadyrov (2011).
CAF-I-dependent control of degradation of the discontinuous strands during mismatch repair.
  Proc Natl Acad Sci U S A, 108, 2753-2758.  
20890269 A.B.Hickman, J.A.James, O.Barabas, C.Pasternak, B.Ton-Hoang, M.Chandler, S.Sommer, and F.Dyda (2010).
DNA recognition and the precleavage state during single-stranded DNA transposition in D. radiodurans.
  EMBO J, 29, 3840-3852.
PDB codes: 2xm3 2xma 2xo6 2xqc
20004149 A.S.Mastrocola, and C.D.Heinen (2010).
Nuclear reorganization of DNA mismatch repair proteins in response to DNA damage.
  DNA Repair (Amst), 9, 120-133.  
20672385 A.S.Mastrocola, and C.D.Heinen (2010).
Lynch syndrome-associated mutations in MSH2 alter DNA repair and checkpoint response functions in vivo.
  Hum Mutat, 31, E1699-E1708.  
20005183 B.Betham, S.Shalhout, V.E.Marquez, and A.S.Bhagwat (2010).
Use of Drosophila deoxynucleoside kinase to study mechanism of toxicity and mutagenicity of deoxycytidine analogs in Escherichia coli.
  DNA Repair (Amst), 9, 153-160.  
20937110 G.Thodi, F.Fostira, R.Sandaltzopoulos, G.Nasioulas, A.Grivas, I.Boukovinas, M.Mylonaki, C.Panopoulos, M.B.Magic, G.Fountzilas, and D.Yannoukakos (2010).
Screening of the DNA mismatch repair genes MLH1, MSH2 and MSH6 in a Greek cohort of Lynch syndrome suspected families.
  BMC Cancer, 10, 544.  
20188637 H.Bai, A.Madabushi, X.Guan, and A.L.Lu (2010).
Interaction between human mismatch repair recognition proteins and checkpoint sensor Rad9-Rad1-Hus1.
  DNA Repair (Amst), 9, 478-487.  
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.  
20167596 J.H.Lebbink, A.Fish, A.Reumer, G.Natrajan, H.H.Winterwerp, and T.K.Sixma (2010).
Magnesium coordination controls the molecular switch function of DNA mismatch repair protein MutS.
  J Biol Chem, 285, 13131-13141.
PDB codes: 2wtu 3k0s
20421420 J.M.Dowen, C.D.Putnam, and R.D.Kolodner (2010).
Functional studies and homology modeling of Msh2-Msh3 predict that mispair recognition involves DNA bending and strand separation.
  Mol Cell Biol, 30, 3321-3328.  
21103398 J.Park, Y.Jeon, D.In, R.Fishel, C.Ban, and J.B.Lee (2010).
Single-molecule analysis reveals the kinetics and physiological relevance of MutL-ssDNA binding.
  PLoS One, 5, e15496.  
  20934970 J.U.Peled, R.S.Sellers, M.D.Iglesias-Ussel, D.M.Shin, C.Montagna, C.Zhao, Z.Li, W.Edelmann, H.C.Morse, and M.D.Scharff (2010).
Msh6 protects mature B cells from lymphoma by preserving genomic stability.
  Am J Pathol, 177, 2597-2608.  
20080735 J.Zhai, and M.M.Hingorani (2010).
Saccharomyces cerevisiae Msh2-Msh6 DNA binding kinetics reveal a mechanism of targeting sites for DNA mismatch repair.
  Proc Natl Acad Sci U S A, 107, 680-685.  
  20725617 K.Fukui (2010).
DNA mismatch repair in eukaryotes and bacteria.
  J Nucleic Acids, 2010, 0.  
  20865162 K.T.Nishant, C.Chen, M.Shinohara, A.Shinohara, and E.Alani (2010).
Genetic analysis of baker's yeast Msh4-Msh5 reveals a threshold crossover level for meiotic viability.
  PLoS Genet, 6, 0.  
20180598 L.E.Sass, C.Lanyi, K.Weninger, and D.A.Erie (2010).
Single-molecule FRET TACKLE reveals highly dynamic mismatched DNA-MutS complexes.
  Biochemistry, 49, 3174-3190.  
  20981145 R.Morita, S.Nakane, A.Shimada, M.Inoue, H.Iino, T.Wakamatsu, K.Fukui, N.Nakagawa, R.Masui, and S.Kuramitsu (2010).
Molecular mechanisms of the whole DNA repair system: a comparison of bacterial and eukaryotic systems.
  J Nucleic Acids, 2010, 179594.  
20154325 R.R.Iyer, A.Pluciennik, J.Genschel, M.S.Tsai, L.S.Beese, and P.Modrich (2010).
MutLalpha and proliferating cell nuclear antigen share binding sites on MutSbeta.
  J Biol Chem, 285, 11730-11739.  
21041657 S.A.Nick McElhinny, G.E.Kissling, and T.A.Kunkel (2010).
Differential correction of lagging-strand replication errors made by DNA polymerases {alpha} and {delta}.
  Proc Natl Acad Sci U S A, 107, 21070-21075.  
20438357 S.Demokan, Y.Suoglu, M.Ulusan, and N.Dalay (2010).
Analysis of the hMSH2 gene variants in head and neck cancer.
  DNA Cell Biol, 29, 449-457.  
19911012 S.Perera, L.Ramyar, A.Mitri, A.Pollett, S.Gallinger, M.D.Speevak, M.Aronson, and B.Bapat (2010).
A novel complex mutation in MSH2 contributes to both Muir-Torre and Lynch Syndrome.
  J Hum Genet, 55, 37-41.  
20567595 S.Roa, Z.Li, J.U.Peled, C.Zhao, W.Edelmann, and M.D.Scharff (2010).
MSH2/MSH6 complex promotes error-free repair of AID-induced dU:G mispairs as well as error-prone hypermutation of A:T sites.
  PLoS One, 5, e11182.  
19237577 A.Mazurek, C.N.Johnson, M.W.Germann, and R.Fishel (2009).
Sequence context effect for hMSH2-hMSH6 mismatch-dependent activation.
  Proc Natl Acad Sci U S A, 106, 4177-4182.  
19282251 A.P.Hayes, L.A.Sevi, M.C.Feldt, M.D.Rose, and A.E.Gammie (2009).
Reciprocal regulation of nuclear import of the yeast MutSalpha DNA mismatch repair proteins Msh2 and Msh6.
  DNA Repair (Amst), 8, 739-751.  
19377479 B.A.Owen, W.H Lang, and C.T.McMurray (2009).
The nucleotide binding dynamics of human MSH2-MSH3 are lesion dependent.
  Nat Struct Mol Biol, 16, 550-557.  
19775280 L.S.Li, J.C.Morales, M.Veigl, D.Sedwick, S.Greer, M.Meyers, M.Wagner, R.Fishel, and D.A.Boothman (2009).
DNA mismatch repair (MMR)-dependent 5-fluorouracil cytotoxicity and the potential for new therapeutic targets.
  Br J Pharmacol, 158, 679-692.  
19228687 L.Tian, L.Gu, and G.M.Li (2009).
Distinct Nucleotide Binding/Hydrolysis Properties and Molar Ratio of MutS{alpha} and MutS{beta} Determine Their Differential Mismatch Binding Activities.
  J Biol Chem, 284, 11557-11562.  
20080788 M.L.Mendillo, V.V.Hargreaves, J.W.Jamison, A.O.Mo, S.Li, C.D.Putnam, V.L.Woods, and R.D.Kolodner (2009).
A conserved MutS homolog connector domain interface interacts with MutL homologs.
  Proc Natl Acad Sci U S A, 106, 22223-22228.  
  19483466 N.Charbonneau, R.Amunugama, C.Schmutte, K.Yoder, and R.Fishel (2009).
Evidence that hMLH3 functions primarily in meiosis and in hMSH2-hMSH3 mismatch repair.
  Cancer Biol Ther, 8, 1411-1420.  
19486659 S.Mukherjee, and M.Feig (2009).
Conformational change in MSH2-MSH6 upon binding DNA coupled to ATPase activity.
  Biophys J, 96, L63-L65.  
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.  
18418867 H.D.McDowell, J.P.Carney, and T.M.Wilson (2008).
Inhibition of the 5' to 3' exonuclease activity of hEXO1 by 8-oxoguanine.
  Environ Mol Mutagen, 49, 388-398.  
18676759 J.A.Maxwell, S.P.Johnson, R.E.McLendon, D.W.Lister, K.S.Horne, A.Rasheed, J.A.Quinn, F.Ali-Osman, A.H.Friedman, P.L.Modrich, D.D.Bigner, and H.S.Friedman (2008).
Mismatch repair deficiency does not mediate clinical resistance to temozolomide in malignant glioma.
  Clin Cancer Res, 14, 4859-4868.  
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.  
18679428 J.Gorman, and E.C.Greene (2008).
Visualizing one-dimensional diffusion of proteins along DNA.
  Nat Struct Mol Biol, 15, 768-774.  
18790734 J.L.Cyr, and C.D.Heinen (2008).
Hereditary Cancer-associated Missense Mutations in hMSH6 Uncouple ATP Hydrolysis from DNA Mismatch Binding.
  J Biol Chem, 283, 31641-31648.  
18304001 J.U.Peled, F.L.Kuang, M.D.Iglesias-Ussel, S.Roa, S.L.Kalis, M.F.Goodman, and M.D.Scharff (2008).
The biochemistry of somatic hypermutation.
  Annu Rev Immunol, 26, 481-511.  
18579505 P.Cejka, and J.Jiricny (2008).
Interplay of DNA repair pathways controls methylation damage toxicity in Saccharomyces cerevisiae.
  Genetics, 179, 1835-1844.  
18406444 P.Hsieh, and K.Yamane (2008).
DNA mismatch repair: molecular mechanism, cancer, and ageing.
  Mech Ageing Dev, 129, 391-407.  
18326858 R.R.Iyer, T.J.Pohlhaus, S.Chen, G.L.Hura, L.Dzantiev, L.S.Beese, and P.Modrich (2008).
The MutSalpha-proliferating cell nuclear antigen interaction in human DNA mismatch repair.
  J Biol Chem, 283, 13310-13319.  
18673453 S.Acharya (2008).
Mutations in the signature motif in MutS affect ATP-induced clamp formation and mismatch repair.
  Mol Microbiol, 69, 1544-1559.  
18773911 S.N.Huang, and D.M.Crothers (2008).
The role of nucleotide cofactor binding in cooperativity and specificity of MutS recognition.
  J Mol Biol, 384, 31-47.  
18951462 S.Ollila, D.Dermadi Bebek, J.Jiricny, and M.Nyström (2008).
Mechanisms of pathogenicity in human MSH2 missense mutants.
  Hum Mutat, 29, 1355-1363.  
18157156 W.Yang (2008).
Structure and mechanism for DNA lesion recognition.
  Cell Res, 18, 184-197.  
17996701 J.Gorman, A.Chowdhury, J.A.Surtees, J.Shimada, D.R.Reichman, E.Alani, and E.C.Greene (2007).
Dynamic basis for one-dimensional DNA scanning by the mismatch repair complex Msh2-Msh6.
  Mol Cell, 28, 359-370.  
18059451 M.M.Hingorani (2007).
TIRF(ing) reveals Msh2-Msh6 surfing on DNA.
  Nat Struct Mol Biol, 14, 1124-1125.  
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.