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References listed in PDB file
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Key reference
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Title
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The dimerization domain of hnf-1alpha: structure and plasticity of an intertwined four-Helix bundle with application to diabetes mellitus.
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Authors
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N.Narayana,
Q.Hua,
M.A.Weiss.
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Ref.
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J Mol Biol, 2001,
310,
635-658.
[DOI no: ]
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PubMed id
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Abstract
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Maturity-onset diabetes mellitus of the young (MODY) is a human genetic syndrome
most commonly due to mutations in hepatocyte nuclear factor-1alpha (HNF-1alpha).
Here, we describe the crystal structure of the HNF-1alpha dimerization domain at
1.7 A resolution and assess its structural plasticity. The crystal's low solvent
content (23%, v/v) leads to tight packing of peptides in the lattice. Two
independent dimers, similar in structure, are formed in the unit cell by a
2-fold crystallographic symmetry axis. The dimers define a novel intertwined
four-helix bundle (4HB). Each protomer contains two alpha-helices separated by a
sharp non-canonical turn. Dimer-related alpha-helices form anti-parallel
coiled-coils, including an N-terminal "mini-zipper" complementary in
structure, symmetry and surface characteristics to transcriptional coactivator
dimerization cofactor of HNF-1 (DCoH). A confluence of ten leucine side-chains
(five per protomer) forms a hydrophobic core. Isotope-assisted NMR studies
demonstrate that a similar intertwined dimer exists in solution. Comparison of
structures obtained in multiple independent crystal forms indicates that the
mini-zipper is a stable structural element, whereas the C-terminal alpha-helix
can adopt a broad range of orientations. Segmental alignment of the mini-zipper
(mean pairwise root-mean-square difference (rmsd) in C(alpha) coordinates of
0.29 A) is associated with a 2.1 A mean C(alpha) rmsd displacement of the
C-terminal coiled-coil. The greatest C-terminal structural variation (4.1 A
C(alpha) rmsd displacement) is observed in the DCoH-bound peptide.
Diabetes-associated mutations perturb distinct structural features of the
HNF-1alpha domain. One mutation (L12H) destabilizes the domain but preserves
structural specificity. Adjoining H12 side-chains in a native-like dimer are
predicted to alter the functional surface of the mini-zipper involved in DCoH
recognition. The other mutation (G20R), by contrast, leads to a dimeric molten
globule, as indicated by its 1H-NMR features and fluorescent binding of
1-anilino-8-naphthalene sulfonate. We propose that a glycine-specific turn
configuration enables specific interactions between the mini-zipper and the
C-terminal coiled-coil.
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Figure 2.
Figure 2. Leucine-rich cluster in HNF-p1w dimer. (a) and
(b) Ribbon representations (related by 180° about the
horizontal axis passing between L12 and L26, and L12' and L26')
of the HNF-p1w dimer. CPK models of leucine side-chains that
form the leucine-rich cluster in core. In one protomer, the
ribbon is shown in black and the leucine residues in red (L12,
MSe13, L16, L21, L26). In the other protomer, the ribbon is
colored gray and leucine side-chains green (L12', MSe13', L16',
L21', L26'). Each protomer contributes four leucine and one
selenomethionine residue. (c) A stereo view of the leucine-rich
cluster shown in (a).
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Figure 10.
Figure 10. Surface representation of HNF-p1w dimer and L12H
homology model. (a) Electrostatic potential of the DCoH-binding
surface of HNF-p1w (stereo pair). The coloring code is red, <
-10 kT/e; white, -10kT/e to 10kT/e; and blue, >10kT/e. Residues
E11 and E18 are involved in ion-pair interactions with DCoH
residues.[35] The exposed concave surface is complementary in
shape to the top of the DCoH saddle as predicted by model
building studies (see the text) and observed in the recent
co-crystal structure. [35] (b) The DCoH-binding surface of
HNF-p1w dimer has a leucine-rich stripe (leucine residues 5, 8,
12, 13, 16 and 21, and their symmetry-related residues) shown in
green. The orientation of molecular surface (white) of the
HNF-p1w dimer is same as in (a). L12 is located in the middle of
the leucine-rich stripe. Residues 1-4 and 1'-4' have been
omitted for clarity. (c)-(e) Homology model of the L12H variant
dimer. (c) The variant side-chain is compatible with a native
overall main-chain fold. One protomer is shown in cyan and the
other in red; terminal residues 1-4 and 1'-4' are disordered in
accord with NMR evidence of flexibility. (d) The structure of
the mini-zipper is predicted to accommodate a pair of histidine
side-chains (yellow) with exposure of polar N  epsilon
ring protons. Neighboring side-chains are in positions similar
to those in crystal structure. (e) The surface of the variant
mini-zipper is predicted to contain a weakly polar protuberance
(yellow) due to the edges of the two His side-chains. This
change in surface character would be expected to perturb DCoH
binding. (a), (b) and (e) Generated using the program GRASP;[85]
(c) and (d) (and other Figures) were made using InsightII (MSI,
Inc., San Diego).
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2001,
310,
635-658)
copyright 2001.
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Secondary reference #1
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Title
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Diabetes-Associated mutations in a beta-Cell transcription factor destabilize an antiparallel "mini-Zipper" in a dimerization interface.
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Authors
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Q.X.Hua,
M.Zhao,
N.Narayana,
S.H.Nakagawa,
W.Jia,
M.A.Weiss.
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Ref.
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Proc Natl Acad Sci U S A, 2000,
97,
1999-2004.
[DOI no: ]
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PubMed id
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Figure 2.
Fig. 2. (A) Upper and lower surfaces of helix-turn-helix
protomer. Shown is a stereo pair showing side chains in the
helix-helix interface (arrow): upper surface (residues 8, 11,
16, 26, and 30; green) and lower surface (residues 5, 9, 13, 17,
21, 23, 24; blue). The side chain of L12 (red) is buried in this
interface. I27 is shown in magenta. The position of G20 C[  ]is
shown as a red sphere. The main chain is shown in gray; carbonyl
oxygens are omitted. (B) Stereo pair showing structure of one
protomer relative to the other (gray ribbon). The coloring
scheme is as in A. One surface of the protomer forms an internal
dimeric interface whereas the other is predicted to bind to
DCoH. Residues 7 and 29 (gray) belong to neither vertical
surface. The view is rotated by 90° from that in A.
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Figure 4.
Fig. 4. Structure of transcriptional coactivator DCoH
(PDB ID code 1dch; refs. 22-24) (A) and model of the DCoH-HNF-1
 complex
(B). (A) The DCoH homotetramer is formed by an antiparallel
dimer of saddles (upper and lower dimers). The lower dimer is
shown in green relative to binding helices (red) of upper dimer
(gray). (B Upper) The tetramer interface of DCoH contains an
antiparallel 4HB (box) with dihedral (D[2]) symmetry. (Lower)
Side view of proposed model of HNF-1 (residues
5-31; red in box) atop the DCoH dimer (green). The predicted
interface's symmetry differs from that of the DCoH-DCoH tetramer.
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Secondary reference #2
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Title
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Structural basis of dimerization, Coactivator recognition and mody3 mutations in hnf-1alpha.
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Authors
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R.B.Rose,
J.H.Bayle,
J.A.Endrizzi,
J.D.Cronk,
G.R.Crabtree,
T.Alber.
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Ref.
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Nat Struct Biol, 2000,
7,
744-748.
[DOI no: ]
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PubMed id
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Figure 1.
Figure 1. Stereo view of the experimental, MAD-phased 2.6 Å
resolution, electron density map contoured at 1  superimposed
on the refined model. Residues 8 -11 in helix 1 of HNF-p1 and
the interacting amino acids of the DCoH dimer (residues 55 -57
and 43' -46', where primes denote residues in the neighboring
subunit) are shown.
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Figure 2.
Figure 2. Structure of the DCoH -HNF-p1 complex. a, The DCoH
dimer (yellow and orange) binds the HNF-p1 dimer (light and dark
blue) with two helix 2 sequences of DCoH in contact with two
helix 1 sequences of HNF-p1. The two-fold rotation axes of the
dimers coincide (arrow). b, The bound HNF-p1 dimer (light and
dark blue) forms an antiparallel four-helix bundle. The view is
along the two-fold rotation axis (+) with the DCoH binding
surface in front. Seven Leu side chains in each monomer
stabilize the dimer and make contacts with DCoH. Red spheres
mark two residues mutated in MODY3 patients, Leu 12 and Gly 20.
The site of a third MODY3 mutation, Gly 31, occurs in the
disordered region of the chain beyond residue 30. c,
Electrostatic potential displayed on the surface of the
recognition helices of DCoH (red, <-2.5 kT/e; white, -2.5 to 2.5
kT/e; and blue, >2.5 kT/e). A stick representation of helix 1 of
the HNF-p1 dimer (light blue) is superimposed on the surface. d,
The corresponding electrostatic potential displayed on the
surface of the HNF-1  recognition
helices. A stick representation of the recognition helices of
the bound DCoH (yellow) is superimposed. The two surfaces in (c)
and (d) match through a 180° rotation about a central, vertical
axis. Complementary positive (DCoH) and negative (HNF-p1)
potentials are evident on the left and right edges of the two
interfaces. e, Interactions between DCoH (yellow and orange) and
HNF-p1 (light and dark blue), viewed along the DCoH helical
axes. Only half of each helix is shown, because the interactions
in the other half are identical. Hydrophobic residues forming
the core of the interface are displayed in gray. Side chains
within hydrogen bonding distance are connected by lines. DCoH
Glu 58' caps the N-terminus of the HNF-p1 helix 1, the Leu 8
amide, and forms a hydrogen bond with Ser 6. DCOH Lys 59' forms
a hydrogen bond to the C-terminus of the neighboring HNF-p1
helix, the carbonyl of Ser 19'.
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The above figures are
reproduced from the cited reference
with permission from Macmillan Publishers Ltd
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Secondary reference #3
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Title
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High-Resolution structure of the hnf-1alpha dimerization domain.
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Authors
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R.B.Rose,
J.A.Endrizzi,
J.D.Cronk,
J.Holton,
T.Alber.
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Ref.
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Biochemistry, 2000,
39,
15062-15070.
[DOI no: ]
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PubMed id
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Secondary reference #4
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Title
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Hnf1, A homeoprotein member of the hepatic transcription regulatory network.
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Authors
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F.Tronche,
M.Yaniv.
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Ref.
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Bioessays, 1992,
14,
579-587.
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PubMed id
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Secondary reference #5
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Title
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Maturity-Onset diabetes of the young (mody), Mody genes and non-Insulin-Dependent diabetes mellitus.
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Authors
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G.Velho,
P.Froguel.
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Ref.
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Diabetes Metab, 1997,
23,
34-37.
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PubMed id
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