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* Residue conservation analysis
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Gene Ontology (GO) functional annotation
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Biological process
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mismatch repair
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1 term
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Biochemical function
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ATP binding
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2 terms
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DOI no:
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Nature
407:703-710
(2000)
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PubMed id:
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Crystal structures of mismatch repair protein MutS and its complex with a substrate DNA.
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G.Obmolova,
C.Ban,
P.Hsieh,
W.Yang.
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ABSTRACT
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DNA mismatch repair is critical for increasing replication fidelity in organisms
ranging from bacteria to humans. MutS protein, a member of the ABC ATPase
superfamily, recognizes mispaired and unpaired bases in duplex DNA and initiates
mismatch repair. Mutations in human MutS genes cause a predisposition to
hereditary nonpolyposis colorectal cancer as well as sporadic tumours. Here we
report the crystal structures of a MutS protein and a complex of MutS with a
heteroduplex DNA containing an unpaired base. The structures reveal the general
architecture of members of the MutS family, an induced-fit mechanism of
recognition between four domains of a MutS dimer and a heteroduplex kinked at
the mismatch, a composite ATPase active site composed of residues from both MutS
subunits, and a transmitter region connecting the mismatch-binding and ATPase
domains. The crystal structures also provide a molecular framework for
understanding hereditary nonpolyposis colorectal cancer mutations and for
postulating testable roles of MutS.
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Selected figure(s)
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Figure 1.
Figure 1: Crystal structure of the TAQ MutS-DNA complex. The
two protein subunits are represented by ribbon diagrams in blue
(A) and green (B). The DNA is shown in a space-filling model, in
which the backbone atoms are red and bases are pink. Three
orthogonal views from the side, front and top are shown.
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Figure 4.
Figure 4: Mismatch recognition by MutS. a, The DNA-binding
domains represented by ribbon diagrams are shown with the
heteroduplex DNA. Domains I and IV of subunit A are shown in
dark blue and orange; the corresponding domains of subunit B are
in light blue and yellow. The DNA phosphate backbones are
represented by red ribbons and sugars and bases are shown as
ball-and-stick. Phe 39 of subunit A is shown in yellow.
Structural elements of subunit B are denoted with a prime. b, A
view from the top of a. c, A 2F[o]- F[c] electron density map
contoured at 1.0 is
shown with the refined structure surrounding the unpaired T. The
unpaired T and the G 5' to it are labelled. Both Phe 39 and Glu
41 belong to subunit A. The dashed lines represent hydrogen
bonds. d, Topology diagram of domains I and IV. Features common
between the two domains are boxed and shown in grey. I B
is replaced by a 3[10] helix in domain IV. e, A diagram of
protein-DNA interactions. Only those base pairs that contact
MutS are shown. Phosphate groups are represented by ovals
between the sugar pentagons. Interactions made by each protein
domain are labelled in the same colour as the ribbon diagram of
this domain in a and b. Hydrogen bonds are represented by red
arrows and van der Waals contacts by blue arrows.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(2000,
407,
703-710)
copyright 2000.
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Figures were
selected
by an automated process.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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PDB code:
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PDB code:
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PDB code:
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PLoS One, 5,
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FEBS J, 277,
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Magnesium coordination controls the molecular switch function of DNA mismatch repair protein MutS.
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J Biol Chem, 285,
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PDB codes:
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J.M.Dowen,
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Functional studies and homology modeling of Msh2-Msh3 predict that mispair recognition involves DNA bending and strand separation.
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Biochemistry, 49,
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A conserved MutS homolog connector domain interface interacts with MutL homologs.
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Proc Natl Acad Sci U S A, 106,
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PDB code:
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G.M.Li
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Cell Res, 18,
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J Biol Chem, 283,
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PDB code:
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Mol Microbiol, 69,
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hMSH4-hMSH5 adenosine nucleotide processing and interactions with homologous recombination machinery.
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J Biol Chem, 283,
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(2008).
Structure and mechanism for DNA lesion recognition.
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Cell Res, 18,
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H.Meng,
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and
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(2008).
The Arabidopsis MutS homolog AtMSH5 is required for normal meiosis.
|
| |
Cell Res, 18,
589-599.
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L.Deterding,
K.B.Tomer,
and
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(2007).
Multiple functions for the N-terminal region of Msh6.
|
| |
Nucleic Acids Res, 35,
4114-4123.
|
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A.E.Gammie,
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B.Devlin,
A.Nanji,
and
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(2007).
Functional characterization of pathogenic human MSH2 missense mutations in Saccharomyces cerevisiae.
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| |
Genetics, 177,
707-721.
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C.A.Rabik,
and
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Molecular mechanisms of resistance and toxicity associated with platinating agents.
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| |
Cancer Treat Rev, 33,
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(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.
|
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E.Jacobs-Palmer,
and
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(2007).
The effects of nucleotides on MutS-DNA binding kinetics clarify the role of MutS ATPase activity in mismatch repair.
|
| |
J Mol Biol, 366,
1087-1098.
|
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|
|
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H.Bai,
and
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(2007).
Physical and functional interactions between Escherichia coli MutY glycosylase and mismatch repair protein MutS.
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E.Alani,
J.Y.Lee,
M.J.Schofield,
A.W.Kijas,
P.Hsieh,
and
W.Yang
(2003).
Crystal structure and biochemical analysis of the MutS.ADP.beryllium fluoride complex suggests a conserved mechanism for ATP interactions in mismatch repair.
|
| |
J Biol Chem, 278,
16088-16094.
|
 |
|
PDB code:
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|
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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.
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| |
Biochemistry, 42,
7682-7693.
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G.H.Toedt,
R.Krishnan,
and
P.Friedhoff
(2003).
Site-specific protein modification to identify the MutL interface of MutH.
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| |
Nucleic Acids Res, 31,
819-825.
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|
|
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G.Natrajan,
M.H.Lamers,
J.H.Enzlin,
H.H.Winterwerp,
A.Perrakis,
and
T.K.Sixma
(2003).
Structures of Escherichia coli DNA mismatch repair enzyme MutS in complex with different mismatches: a common recognition mode for diverse substrates.
|
| |
Nucleic Acids Res, 31,
4814-4821.
|
 |
|
PDB codes:
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|
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H.C.Ahn,
T.Ohkubo,
S.Iwai,
K.Morikawa,
and
B.J.Lee
(2003).
Interaction of T4 endonuclease V with DNA: importance of the flexible loop regions in protein-DNA interaction.
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| |
J Biol Chem, 278,
30985-30992.
|
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|
|
|
|
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H.Wang,
Y.Yang,
M.J.Schofield,
C.Du,
Y.Fridman,
S.D.Lee,
E.D.Larson,
J.T.Drummond,
E.Alani,
P.Hsieh,
and
D.A.Erie
(2003).
DNA bending and unbending by MutS govern mismatch recognition and specificity.
|
| |
Proc Natl Acad Sci U S A, 100,
14822-14827.
|
 |
|
|
|
|
 |
K.A.Bunting,
S.M.Roe,
A.Headley,
T.Brown,
R.Savva,
and
L.H.Pearl
(2003).
Crystal structure of the Escherichia coli dcm very-short-patch DNA repair endonuclease bound to its reaction product-site in a DNA superhelix.
|
| |
Nucleic Acids Res, 31,
1633-1639.
|
 |
|
PDB code:
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K.P.Bjornson,
L.J.Blackwell,
H.Sage,
C.Baitinger,
D.Allen,
and
P.Modrich
(2003).
Assembly and molecular activities of the MutS tetramer.
|
| |
J Biol Chem, 278,
34667-34673.
|
 |
|
|
|
|
 |
K.P.Bjornson,
and
P.Modrich
(2003).
Differential and simultaneous adenosine di- and triphosphate binding by MutS.
|
| |
J Biol Chem, 278,
18557-18562.
|
 |
|
|
|
|
 |
K.S.McKeegan,
M.I.Borges-Walmsley,
and
A.R.Walmsley
(2003).
The structure and function of drug pumps: an update.
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| |
Trends Microbiol, 11,
21-29.
|
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|
|
|
|
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L.Augusto-Pinto,
S.M.Teixeira,
S.D.Pena,
and
C.R.Machado
(2003).
Single-nucleotide polymorphisms of the Trypanosoma cruzi MSH2 gene support the existence of three phylogenetic lineages presenting differences in mismatch-repair efficiency.
|
| |
Genetics, 164,
117-126.
|
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|
|
|
|
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M.H.Lamers,
H.H.Winterwerp,
and
T.K.Sixma
(2003).
The alternating ATPase domains of MutS control DNA mismatch repair.
|
| |
EMBO J, 22,
746-756.
|
 |
|
PDB code:
|
 |
|
|
|
|
|
 |
M.J.Schofield,
and
P.Hsieh
(2003).
DNA mismatch repair: molecular mechanisms and biological function.
|
| |
Annu Rev Microbiol, 57,
579-608.
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|
|
|
|
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P.J.Lau,
and
R.D.Kolodner
(2003).
Transfer of the MSH2.MSH6 complex from proliferating cell nuclear antigen to mispaired bases in DNA.
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| |
J Biol Chem, 278,
14-17.
|
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|
|
|
|
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P.Peterlongo,
K.Nafa,
G.S.Lerman,
E.Glogowski,
J.Shia,
T.Z.Ye,
A.J.Markowitz,
J.G.Guillem,
P.Kolachana,
J.A.Boyd,
K.Offit,
and
N.A.Ellis
(2003).
MSH6 germline mutations are rare in colorectal cancer families.
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| |
Int J Cancer, 107,
571-579.
|
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|
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|
|
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R.J.Willems,
J.Top,
D.J.Smith,
D.I.Roper,
S.E.North,
and
N.Woodford
(2003).
Mutations in the DNA mismatch repair proteins MutS and MutL of oxazolidinone-resistant or -susceptible Enterococcus faecium.
|
| |
Antimicrob Agents Chemother, 47,
3061-3066.
|
 |
|
|
|
|
 |
R.V.Abdelnoor,
R.Yule,
A.Elo,
A.C.Christensen,
G.Meyer-Gauen,
and
S.A.Mackenzie
(2003).
Substoichiometric shifting in the plant mitochondrial genome is influenced by a gene homologous to MutS.
|
| |
Proc Natl Acad Sci U S A, 100,
5968-5973.
|
 |
|
|
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|
 |
S.Acharya,
P.L.Foster,
P.Brooks,
and
R.Fishel
(2003).
The coordinated functions of the E. coli MutS and MutL proteins in mismatch repair.
|
| |
Mol Cell, 12,
233-246.
|
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|
|
|
|
 |
S.Y.Wu,
K.Culligan,
M.Lamers,
and
J.Hays
(2003).
Dissimilar mispair-recognition spectra of Arabidopsis DNA-mismatch-repair proteins MSH2*MSH6 (MutSalpha) and MSH2*MSH7 (MutSgamma).
|
| |
Nucleic Acids Res, 31,
6027-6034.
|
 |
|
|
|
|
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A.Mazurek,
M.Berardini,
and
R.Fishel
(2002).
Activation of human MutS homologs by 8-oxo-guanine DNA damage.
|
| |
J Biol Chem, 277,
8260-8266.
|
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|
|
|
|
 |
A.S.Bhagwat,
and
M.Lieb
(2002).
Cooperation and competition in mismatch repair: very short-patch repair and methyl-directed mismatch repair in Escherichia coli.
|
| |
Mol Microbiol, 44,
1421-1428.
|
 |
|
|
|
|
 |
C.D.Heinen,
T.Wilson,
A.Mazurek,
M.Berardini,
C.Butz,
and
R.Fishel
(2002).
HNPCC mutations in hMSH2 result in reduced hMSH2-hMSH6 molecular switch functions.
|
| |
Cancer Cell, 1,
469-478.
|
 |
|
|
|
|
 |
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.
|
 |
|
|
|
|
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G.Plotz,
J.Raedle,
A.Brieger,
J.Trojan,
and
S.Zeuzem
(2002).
hMutSalpha forms an ATP-dependent complex with hMutLalpha and hMutLbeta on DNA.
|
| |
Nucleic Acids Res, 30,
711-718.
|
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|
|
|
|
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J.C.Shiels,
J.B.Tuite,
S.J.Nolan,
and
A.M.Baranger
(2002).
Investigation of a conserved stacking interaction in target site recognition by the U1A protein.
|
| |
Nucleic Acids Res, 30,
550-558.
|
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|
|
|
|
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K.Drotschmann,
M.C.Hall,
P.V.Shcherbakova,
H.Wang,
D.A.Erie,
F.R.Brownewell,
E.T.Kool,
and
T.A.Kunkel
(2002).
DNA binding properties of the yeast Msh2-Msh6 and Mlh1-Pms1 heterodimers.
|
| |
Biol Chem, 383,
969-975.
|
 |
|
|
|
|
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K.P.Hopfner,
C.D.Putnam,
and
J.A.Tainer
(2002).
DNA double-strand break repair from head to tail.
|
| |
Curr Opin Struct Biol, 12,
115-122.
|
 |
|
|
|
|
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M.T.Hess,
R.D.Gupta,
and
R.D.Kolodner
(2002).
Dominant Saccharomyces cerevisiae msh6 mutations cause increased mispair binding and decreased dissociation from mispairs by Msh2-Msh6 in the presence of ATP.
|
| |
J Biol Chem, 277,
25545-25553.
|
 |
|
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|
 |
N.S.Frolova,
N.Schek,
N.Tikhmyanova,
and
T.R.Coleman
(2002).
Xenopus Cdc6 performs separate functions in initiating DNA replication.
|
| |
Mol Biol Cell, 13,
1298-1312.
|
 |
|
|
|
|
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T.M.Marti,
C.Kunz,
and
O.Fleck
(2002).
DNA mismatch repair and mutation avoidance pathways.
|
| |
J Cell Physiol, 191,
28-41.
|
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|
|
|
|
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W.D.Foulkes,
I.Thiffault,
S.B.Gruber,
M.Horwitz,
N.Hamel,
C.Lee,
J.Shia,
A.Markowitz,
A.Figer,
E.Friedman,
D.Farber,
C.M.Greenwood,
J.D.Bonner,
K.Nafa,
T.Walsh,
V.Marcus,
L.Tomsho,
J.Gebert,
F.A.Macrae,
C.L.Gaff,
B.B.Paillerets,
P.K.Gregersen,
J.N.Weitzel,
P.H.Gordon,
E.MacNamara,
M.C.King,
H.Hampel,
A.De La Chapelle,
J.Boyd,
K.Offit,
G.Rennert,
G.Chong,
and
N.A.Ellis
(2002).
The founder mutation MSH2*1906G-->C is an important cause of hereditary nonpolyposis colorectal cancer in the Ashkenazi Jewish population.
|
| |
Am J Hum Genet, 71,
1395-1412.
|
 |
|
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|
 |
A.Guarné,
M.S.Junop,
and
W.Yang
(2001).
Structure and function of the N-terminal 40 kDa fragment of human PMS2: a monomeric GHL ATPase.
|
| |
EMBO J, 20,
5521-5531.
|
 |
|
PDB codes:
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|
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A.Joshi,
and
B.J.Rao
(2001).
MutS recognition: multiple mismatches and sequence context effects.
|
| |
J Biosci, 26,
595-606.
|
 |
|
|
|
|
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C.Geourjon,
C.Orelle,
E.Steinfels,
C.Blanchet,
G.Deléage,
A.Di Pietro,
and
J.M.Jault
(2001).
A common mechanism for ATP hydrolysis in ABC transporter and helicase superfamilies.
|
| |
Trends Biochem Sci, 26,
539-544.
|
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|
|
|
|
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D.Baker,
and
A.Sali
(2001).
Protein structure prediction and structural genomics.
|
| |
Science, 294,
93-96.
|
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|
|
|
|
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D.M.Young,
and
L.N.Ornston
(2001).
Functions of the mismatch repair gene mutS from Acinetobacter sp. strain ADP1.
|
| |
J Bacteriol, 183,
6822-6831.
|
 |
|
|
|
|
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E.A.Sia,
M.Dominska,
L.Stefanovic,
and
T.D.Petes
(2001).
Isolation and characterization of point mutations in mismatch repair genes that destabilize microsatellites in yeast.
|
| |
Mol Cell Biol, 21,
8157-8167.
|
 |
|
|
|
|
 |
F.J.López de Saro,
and
M.O'Donnell
(2001).
Interaction of the beta sliding clamp with MutS, ligase, and DNA polymerase I.
|
| |
Proc Natl Acad Sci U S A, 98,
8376-8380.
|
 |
|
|
|
|
 |
H.Ling,
F.Boudsocq,
R.Woodgate,
and
W.Yang
(2001).
Crystal structure of a Y-family DNA polymerase in action: a mechanism for error-prone and lesion-bypass replication.
|
| |
Cell, 107,
91.
|
 |
|
PDB codes:
|
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|
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|
 |
J.A.Irving,
and
A.G.Hall
(2001).
Mismatch repair defects as a cause of resistance to cytotoxic drugs.
|
| |
Expert Rev Anticancer Ther, 1,
149-158.
|
 |
|
|
|
|
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K.Drotschmann,
W.Yang,
F.E.Brownewell,
E.T.Kool,
and
T.A.Kunkel
(2001).
Asymmetric recognition of DNA local distortion. Structure-based functional studies of eukaryotic Msh2-Msh6.
|
| |
J Biol Chem, 276,
46225-46229.
|
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|
|
|
|
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K.P.Hopfner,
A.Karcher,
L.Craig,
T.T.Woo,
J.P.Carney,
and
J.A.Tainer
(2001).
Structural biochemistry and interaction architecture of the DNA double-strand break repair Mre11 nuclease and Rad50-ATPase.
|
| |
Cell, 105,
473-485.
|
 |
|
PDB codes:
|
 |
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|
 |
M.J.Schofield,
F.E.Brownewell,
S.Nayak,
C.Du,
E.T.Kool,
and
P.Hsieh
(2001).
The Phe-X-Glu DNA binding motif of MutS. The role of hydrogen bonding in mismatch recognition.
|
| |
J Biol Chem, 276,
45505-45508.
|
 |
|
|
|
|
 |
M.J.Sippl,
P.Lackner,
F.S.Domingues,
A.Prlić,
R.Malik,
A.Andreeva,
and
M.Wiederstein
(2001).
Assessment of the CASP4 fold recognition category.
|
| |
Proteins, 0,
55-67.
|
 |
|
|
|
|
 |
M.Lieb,
S.Rehmat,
and
A.S.Bhagwat
(2001).
Interaction of MutS and Vsr: some dominant-negative mutS mutations that disable methyladenine-directed mismatch repair are active in very-short-patch repair.
|
| |
J Bacteriol, 183,
6487-6490.
|
 |
|
|
|
|
 |
M.S.Junop,
G.Obmolova,
K.Rausch,
P.Hsieh,
and
W.Yang
(2001).
Composite active site of an ABC ATPase: MutS uses ATP to verify mismatch recognition and authorize DNA repair.
|
| |
Mol Cell, 7,
1.
|
 |
|
PDB code:
|
 |
|
|
|
|
|
 |
R.Gaudet,
and
D.C.Wiley
(2001).
Structure of the ABC ATPase domain of human TAP1, the transporter associated with antigen processing.
|
| |
EMBO J, 20,
4964-4972.
|
 |
|
PDB code:
|
 |
|
|
|
|
|
 |
J.Jiricny
(2000).
Mismatch repair: the praying hands of fidelity.
|
| |
Curr Biol, 10,
R788-R790.
|
 |
|
|
|
|
 |
K.P.Hopfner,
and
J.A.Tainer
(2000).
DNA mismatch repair: the hands of a genome guardian.
|
| |
Structure, 8,
R237-R241.
|
 |
|
 |
 |
|
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.
|
|