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* Residue conservation analysis
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PDB id:
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Transcription/DNA
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Title:
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Crystal structure of runx-1/aml1/cbfalpha runt domain and c/ebpbeta bzip homodimer bound to a DNA fragment from the csf-1r promoter
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Structure:
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Ccaat/enhancer binding protein beta. Chain: a, b, d, e. Fragment: residues 259-345. Synonym: c/ebp beta, nfil-6. Engineered: yes. Runt-related transcription factor 1. Chain: c, f. Fragment: residues 60-182. Synonym: core binding factor alpha, runx-1, aml1, pebp2alphab, cbfa2.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008. Mus musculus. Mouse. Organism_taxid: 10090. Synthetic: yes.
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Biol. unit:
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Hetero-Pentamer (from PDB file)
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Resolution:
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3.00Å
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R-factor:
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0.244
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R-free:
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0.313
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Authors:
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T.H.Tahirov,K.Ogata
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Key ref:
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T.H.Tahirov
et al.
(2001).
Structural analyses of DNA recognition by the AML1/Runx-1 Runt domain and its allosteric control by CBFbeta.
Cell,
104,
755-767.
PubMed id:
DOI:
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Date:
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11-Jan-01
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Release date:
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09-Mar-01
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PROCHECK
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Headers
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References
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DOI no:
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Cell
104:755-767
(2001)
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PubMed id:
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Structural analyses of DNA recognition by the AML1/Runx-1 Runt domain and its allosteric control by CBFbeta.
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T.H.Tahirov,
T.Inoue-Bungo,
H.Morii,
A.Fujikawa,
M.Sasaki,
K.Kimura,
M.Shiina,
K.Sato,
T.Kumasaka,
M.Yamamoto,
S.Ishii,
K.Ogata.
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ABSTRACT
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The core binding factor (CBF) heterodimeric transcription factors comprised of
AML/CBFA/PEBP2alpha/Runx and CBFbeta/PEBP2beta subunits are essential for
differentiation of hematopoietic and bone cells, and their mutation is
intimately related to the development of acute leukemias and cleidocranial
dysplasia. Here, we present the crystal structures of the
AML1/Runx-1/CBFalpha(Runt domain)-CBFbeta(core domain)-C/EBPbeta(bZip)-DNA,
AML1/Runx-1/CBFalpha(Runt domain)-C/EBPbeta(bZip)-DNA, and
AML1/Runx-1/CBFalpha(Runt domain)-DNA complexes. The hydrogen bonding network
formed among CBFalpha(Runt domain) and CBFbeta, and CBFalpha(Runt domain) and
DNA revealed the allosteric regulation mechanism of CBFalpha(Runt domain)-DNA
binding by CBFbeta. The point mutations of CBFalpha related to the
aforementioned diseases were also mapped and their effect on DNA binding is
discussed.
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Selected figure(s)
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Figure 1.
Figure 1. Overviews of the CBFα-β-C/EBPβ-DNA Quarternary
Complex from Three PerspectivesViews from the front (A), from
the side (B), and from the top (C). Within CBFα, β strands,
and loops are depicted as red arrows and pink tubes,
respectively; within CBFβ, α helices, β strands, and loops
are depicted as green ribbons, blue arrows, and cyan tubes,
respectively. The C-terminal region of the C/EBPβ homodimer
containing the bZip domain is shown as yellow ribbons
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Figure 2.
Figure 2. Sequences, Foldings, and DNA Recognition(A) Amino
acid sequences of CBFα and CBFβ with indications of their
secondary structures; the nucleotide sequence of the 26 bp
double-stranded DNA fragment used for determining the structures
of the CBFα-β-C/EBPβ-DNA and CBFα-C/EBPβ-DNA complexes; and
the sequence of the 16 bp DNA fragment used for determining the
structure of the CBFα-DNA complex.(B and C) Topology diagrams
of the structures of CBFα (B) and CBFβ (C). The first and last
residue numbers of each secondary structure are indicated. The
notations A, B, C, C′, E, F, and G correspond to the β
strands classified as being within the immunoglobulin fold. In
(B), cyan, green, and yellow circles depict the residues
involved in specific DNA base recognition, nonspecific DNA
backbone interactions, and water-mediated interactions,
respectively. In (C), the electron density of a section of L3
(residues 71 to 81) was not observed (dotted line).(D) Schematic
representation of DNA recognition by CBFα. Dashed and solid
lines depict intermolecular hydrogen bonds and van der Waals
contacts, respectively. DNA base labels involved in direct
interactions with amino acids are colored red. A DNA base label
involved in water-mediated base recognitions is colored green.
DNA recognitions by the peptide backbone amide are noted as NH.
Minor groove recognitions are circled with magenta.(E) A stereo
view of the specific interactions between CBFα and DNA. Pink
tubes show the CBFα peptide backbone. Dotted lines depict
intermolecular hydrogen bonds and water molecules are shown as
red balls
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The above figures are
reprinted
by permission from Cell Press:
Cell
(2001,
104,
755-767)
copyright 2001.
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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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W.Zhang,
J.Du,
S.L.Evans,
Y.Yu,
and
X.F.Yu
(2012).
T-cell differentiation factor CBF-β regulates HIV-1 Vif-mediated evasion of host restriction.
|
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Nature,
481,
376-379.
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|
|
|
|
|
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A.Puig-Kröger,
N.Aguilera-Montilla,
R.Martínez-Nuñez,
A.Domínguez-Soto,
F.Sánchez-Cabo,
E.Martín-Gayo,
A.Zaballos,
M.L.Toribio,
Y.Groner,
Y.Ito,
A.Dopazo,
M.T.Corcuera,
M.J.Alonso Martín,
M.A.Vega,
and
A.L.Corbí
(2010).
The novel RUNX3/p33 isoform is induced upon monocyte-derived dendritic cell maturation and downregulates IL-8 expression.
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Immunobiology,
215,
812-820.
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C.Wichmann,
Y.Becker,
L.Chen-Wichmann,
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J.Herglotz,
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J.Koch,
J.Lausen,
W.Mäntele,
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and
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(2010).
Dimer-tetramer transition controls RUNX1/ETO leukemogenic activity.
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Blood,
116,
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C.Zhang,
S.Zheng,
Y.Wang,
Y.Zhao,
J.Zhu,
and
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(2010).
Mutational analysis of RUNX2 gene in Chinese patients with cleidocranial dysplasia.
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Mutagenesis,
25,
589-594.
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D.Mendoza-Villanueva,
W.Deng,
C.Lopez-Camacho,
and
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(2010).
The Runx transcriptional co-activator, CBFbeta, is essential for invasion of breast cancer cells.
|
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Mol Cancer,
9,
171.
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R.Rohs,
X.Jin,
S.M.West,
R.Joshi,
B.Honig,
and
R.S.Mann
(2010).
Origins of specificity in protein-DNA recognition.
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Annu Rev Biochem,
79,
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S.K.Baniwal,
O.Khalid,
Y.Gabet,
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and
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Runx2 transcriptome of prostate cancer cells: insights into invasiveness and bone metastasis.
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Mol Cancer,
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S.R.Bowers,
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and
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(2010).
Runx1 binds as a dimeric complex to overlapping Runx1 sites within a palindromic element in the human GM-CSF enhancer.
|
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Nucleic Acids Res,
38,
6124-6134.
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T.Ernst,
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A.Hochhaus,
and
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(2010).
Transcription factor mutations in myelodysplastic/myeloproliferative neoplasms.
|
| |
Haematologica,
95,
1473-1480.
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C.M.McDonald,
C.Petosa,
and
P.J.Farrell
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Interaction of Epstein-Barr virus BZLF1 C-terminal tail structure and core zipper is required for DNA replication but not for promoter transactivation.
|
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J Virol,
83,
3397-3401.
|
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|
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D.Rudra,
T.Egawa,
M.M.Chong,
P.Treuting,
D.R.Littman,
and
A.Y.Rudensky
(2009).
Runx-CBFbeta complexes control expression of the transcription factor Foxp3 in regulatory T cells.
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Nat Immunol,
10,
1170-1177.
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G.Brady,
and
P.J.Farrell
(2009).
RUNX3-mediated repression of RUNX1 in B cells.
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J Cell Physiol,
221,
283-287.
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H.Huang,
M.Yu,
T.E.Akie,
T.B.Moran,
A.J.Woo,
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and
A.B.Cantor
(2009).
Differentiation-dependent interactions between RUNX-1 and FLI-1 during megakaryocyte development.
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Mol Cell Biol,
29,
4103-4115.
|
|
|
|
|
|
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J.L.Barton,
D.H.Bunka,
S.E.Knowling,
P.Lefevre,
A.J.Warren,
C.Bonifer,
and
P.G.Stockley
(2009).
Characterization of RNA aptamers that disrupt the RUNX1-CBFbeta/DNA complex.
|
| |
Nucleic Acids Res,
37,
6818-6830.
|
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|
|
|
|
|
J.L.Tang,
H.A.Hou,
C.Y.Chen,
C.Y.Liu,
W.C.Chou,
M.H.Tseng,
C.F.Huang,
F.Y.Lee,
M.C.Liu,
M.Yao,
S.Y.Huang,
B.S.Ko,
S.C.Hsu,
S.J.Wu,
W.Tsay,
Y.C.Chen,
L.I.Lin,
and
H.F.Tien
(2009).
AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations.
|
| |
Blood,
114,
5352-5361.
|
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|
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J.W.Locasale,
A.A.Napoli,
S.Chen,
H.M.Berman,
and
C.L.Lawson
(2009).
Signatures of protein-DNA recognition in free DNA binding sites.
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J Mol Biol,
386,
1054-1065.
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PDB codes:
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L.Roudaia,
M.D.Cheney,
E.Manuylova,
W.Chen,
M.Morrow,
S.Park,
C.T.Lee,
P.Kaur,
O.Williams,
J.H.Bushweller,
and
N.A.Speck
(2009).
CBFbeta is critical for AML1-ETO and TEL-AML1 activity.
|
| |
Blood,
113,
3070-3079.
|
|
|
|
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|
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X.Z.Chi,
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Y.H.Lee,
J.W.Lee,
K.S.Lee,
H.Wee,
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B.C.Oh,
G.S.Stein,
Y.Ito,
A.J.van Wijnen,
and
S.C.Bae
(2009).
Runt-related transcription factor RUNX3 is a target of MDM2-mediated ubiquitination.
|
| |
Cancer Res,
69,
8111-8119.
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A.M.Müller,
J.Duque,
J.A.Shizuru,
and
M.Lübbert
(2008).
Complementing mutations in core binding factor leukemias: from mouse models to clinical applications.
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Oncogene,
27,
5759-5773.
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M.Gao,
and
J.Skolnick
(2008).
DBD-Hunter: a knowledge-based method for the prediction of DNA-protein interactions.
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Nucleic Acids Res,
36,
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R.R.Copley
(2008).
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Philos Trans R Soc Lond B Biol Sci,
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T.Yokomizo,
M.Yanagida,
G.Huang,
M.Osato,
C.Honda,
M.Ema,
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M.Yamamoto,
and
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(2008).
Genetic evidence of PEBP2beta-independent activation of Runx1 in the murine embryo.
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| |
Int J Hematol,
88,
134-138.
|
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C.J.Matheny,
M.E.Speck,
P.R.Cushing,
Y.Zhou,
T.Corpora,
M.Regan,
M.Newman,
L.Roudaia,
C.L.Speck,
T.L.Gu,
S.M.Griffey,
J.H.Bushweller,
and
N.A.Speck
(2007).
Disease mutations in RUNX1 and RUNX2 create nonfunctional, dominant-negative, or hypomorphic alleles.
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EMBO J,
26,
1163-1175.
|
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|
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C.Y.Lien,
O.K.Lee,
and
Y.Su
(2007).
Cbfb enhances the osteogenic differentiation of both human and mouse mesenchymal stem cells induced by Cbfa-1 via reducing its ubiquitination-mediated degradation.
|
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Stem Cells,
25,
1462-1468.
|
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F.Dicker,
C.Haferlach,
W.Kern,
T.Haferlach,
and
S.Schnittger
(2007).
Trisomy 13 is strongly associated with AML1/RUNX1 mutations and increased FLT3 expression in acute myeloid leukemia.
|
| |
Blood,
110,
1308-1316.
|
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H.Agerstam,
H.Lilljebjörn,
C.Lassen,
A.Swedin,
J.Richter,
P.Vandenberghe,
B.Johansson,
and
T.Fioretos
(2007).
Fusion gene-mediated truncation of RUNX1 as a potential mechanism underlying disease progression in the 8p11 myeloproliferative syndrome.
|
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Genes Chromosomes Cancer,
46,
635-643.
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H.Kagoshima,
K.Shigesada,
and
Y.Kohara
(2007).
RUNX regulates stem cell proliferation and differentiation: insights from studies of C. elegans.
|
| |
J Cell Biochem,
100,
1119-1130.
|
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L.Zhao,
J.L.Cannons,
S.Anderson,
M.Kirby,
L.Xu,
L.H.Castilla,
P.L.Schwartzberg,
R.Bosselut,
and
P.P.Liu
(2007).
CBFB-MYH11 hinders early T-cell development and induces massive cell death in the thymus.
|
| |
Blood,
109,
3432-3440.
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S.Tang,
Q.Xu,
X.Xu,
J.Du,
X.Yang,
Y.Jiang,
X.Wang,
N.Speck,
and
T.Huang
(2007).
A novel RUNX2 missense mutation predicted to disrupt DNA binding causes cleidocranial dysplasia in a large Chinese family with hyperplastic nails.
|
| |
BMC Med Genet,
8,
82.
|
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|
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Y.Liu,
W.Chen,
J.Gaudet,
M.D.Cheney,
L.Roudaia,
T.Cierpicki,
R.C.Klet,
K.Hartman,
T.M.Laue,
N.A.Speck,
and
J.H.Bushweller
(2007).
Structural basis for recognition of SMRT/N-CoR by the MYND domain and its contribution to AML1/ETO's activity.
|
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Cancer Cell,
11,
483-497.
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PDB codes:
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A.J.Robertson,
C.Dickey-Sims,
A.Ransick,
D.E.Rupp,
J.J.McCarthy,
and
J.A.Coffman
(2006).
CBFbeta is a facultative Runx partner in the sea urchin embryo.
|
| |
BMC Biol,
4,
4.
|
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B.M.Schaubach,
H.Y.Wen,
and
R.E.Kellems
(2006).
Regulation of murine Ada gene expression in the placenta by transcription factor RUNX1.
|
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Placenta,
27,
269-277.
|
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|
|
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F.M.Mikhail,
K.K.Sinha,
Y.Saunthararajah,
and
G.Nucifora
(2006).
Normal and transforming functions of RUNX1: a perspective.
|
| |
J Cell Physiol,
207,
582-593.
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H.Liu,
L.Carlsson,
and
T.Grundström
(2006).
Identification of an N-terminal transactivation domain of Runx1 that separates molecular function from global differentiation function.
|
| |
J Biol Chem,
281,
25659-25669.
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J.S.Lamoureux,
and
J.N.Glover
(2006).
Principles of protein-DNA recognition revealed in the structural analysis of Ndt80-MSE DNA complexes.
|
| |
Structure,
14,
555-565.
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PDB codes:
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|
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Z.Li,
S.M.Lukasik,
Y.Liu,
J.Grembecka,
I.Bielnicka,
J.H.Bushweller,
and
N.A.Speck
(2006).
A mutation in the S-switch region of the Runt domain alters the dynamics of an allosteric network responsible for CBFbeta regulation.
|
| |
J Mol Biol,
364,
1073-1083.
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PDB code:
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B.Habtemariam,
V.M.Anisimov,
and
A.D.MacKerell
(2005).
Cooperative binding of DNA and CBFbeta to the Runt domain of the CBFalpha studied via MD simulations.
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| |
Nucleic Acids Res,
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C.K.Inman,
N.Li,
and
P.Shore
(2005).
Oct-1 counteracts autoinhibition of Runx2 DNA binding to form a novel Runx2/Oct-1 complex on the promoter of the mammary gland-specific gene beta-casein.
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Mol Cell Biol,
25,
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I.Moreno-Miralles,
L.Pan,
J.Keates-Baleeiro,
K.Durst-Goodwin,
C.Yang,
H.G.Kim,
M.A.Thompson,
C.A.Klug,
J.L.Cleveland,
and
S.W.Hiebert
(2005).
The inv(16) cooperates with ARF haploinsufficiency to induce acute myeloid leukemia.
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J Biol Chem,
280,
40097-40103.
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J.P.Pinto,
N.M.Conceição,
C.S.Viegas,
R.B.Leite,
L.D.Hurst,
R.N.Kelsh,
and
M.L.Cancela
(2005).
Identification of a new pebp2alphaA2 isoform from zebrafish runx2 capable of inducing osteocalcin gene expression in vitro.
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| |
J Bone Miner Res,
20,
1440-1453.
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K.Blyth,
E.R.Cameron,
and
J.C.Neil
(2005).
The RUNX genes: gain or loss of function in cancer.
|
| |
Nat Rev Cancer,
5,
376-387.
|
|
|
|
|
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|
K.Cartharius,
K.Frech,
K.Grote,
B.Klocke,
M.Haltmeier,
A.Klingenhoff,
M.Frisch,
M.Bayerlein,
and
T.Werner
(2005).
MatInspector and beyond: promoter analysis based on transcription factor binding sites.
|
| |
Bioinformatics,
21,
2933-2942.
|
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M.Kitayner,
H.Rozenberg,
D.Rabinovich,
and
Z.Shakked
(2005).
Structures of the DNA-binding site of Runt-domain transcription regulators.
|
| |
Acta Crystallogr D Biol Crystallogr,
61,
236-246.
|
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PDB codes:
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N.Yoshida,
T.Ogata,
K.Tanabe,
S.Li,
M.Nakazato,
K.Kohu,
T.Takafuta,
S.Shapiro,
Y.Ohta,
M.Satake,
and
T.Watanabe
(2005).
Filamin A-bound PEBP2beta/CBFbeta is retained in the cytoplasm and prevented from functioning as a partner of the Runx1 transcription factor.
|
| |
Mol Cell Biol,
25,
1003-1012.
|
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T.M.Schroeder,
E.D.Jensen,
and
J.J.Westendorf
(2005).
Runx2: a master organizer of gene transcription in developing and maturing osteoblasts.
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PDB code:
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Nat Genet,
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PDB code:
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J.Miller,
A.Horner,
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PDB codes:
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PDB code:
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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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