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PDBsum entry 1l8c
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Gene regulation
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PDB id
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1l8c
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structural basis for hif-1 alpha /cbp recognition in the cellular hypoxic response.
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Authors
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S.A.Dames,
M.Martinez-Yamout,
R.N.De guzman,
H.J.Dyson,
P.E.Wright.
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Ref.
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Proc Natl Acad Sci U S A, 2002,
99,
5271-5276.
[DOI no: ]
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PubMed id
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Abstract
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The cellular response to low tissue oxygen concentrations is mediated by the
hypoxia-inducible transcription factor HIF-1. Under hypoxic conditions, HIF-1
activates transcription of critical adaptive genes by recruitment of the general
coactivators CBP/p300 through interactions with its alpha-subunit (Hif-1 alpha).
Disruption of the Hif-1 alpha/p300 interaction has been linked to attenuation of
tumor growth. To delineate the structural basis for this interaction, we have
determined the solution structure of the complex between the carboxy-terminal
activation domain (CAD) of Hif-1 alpha and the zinc-binding TAZ1 (CH1) motif of
cyclic-AMP response element binding protein (CREB) binding protein (CBP).
Despite the overall similarity of the TAZ1 structure to that of the TAZ2 (part
of the CH3) domain of CBP, differences occur in the packing of helices that can
account for differences in specificity. The unbound CAD is intrinsically
disordered and remains relatively extended upon binding, wrapping almost
entirely around the TAZ1 domain in a groove through much of its surface. Three
short helices are formed upon binding, stabilized by intermolecular
interactions. The Asn-803 side chain, which functions as a hypoxic switch, is
located on the second of these helices and is buried in the molecular interface.
The third helix of the Hif-1 alpha CAD docks in a deep hydrophobic groove in
TAZ1, providing extensive intermolecular hydrophobic interactions that
contribute to the stability of the complex. The structure of this complex
provides new insights into the mechanism through which Hif-1 alpha recruits
CBP/p300 in response to hypoxia.
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Figure 1.
Fig. 1. 1H-15N heteronuclear single quantum coherence
spectra (600 MHz) of Hif-1  (776-826)
free (red) and bound to unlabeled TAZ1 (black).
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Figure 2.
Fig. 2. NMR structure of the Hif-1 :TAZ1
complex. (A) Stereo view of the best 20 structures superposed on
backbone heavy atoms in ordered regions. The TAZ1 backbone is
shown in blue, Hif-1 in pink,
and the N and C termini of each chain are labeled in the
corresponding colors. Bound zinc ions are shown as yellow
spheres. (B) Ribbon representation of a single structure in a
similar orientation to A. Helices [1]- [4] of TAZ1
and [A]- [C] of the
Hif-1 CAD are
labeled. The zinc ions are represented as white spheres, and the
side chains of the cysteine and histidine ligands are shown in
yellow and blue, respectively.
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