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PDBsum entry 1l8c
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protein metals Protein-protein interface(s) links
Gene regulation PDB id
1l8c

 

 

 

 

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JSmol PyMol  
Contents
Protein chains
95 a.a. *
51 a.a. *
Metals
_ZN ×3
* Residue conservation analysis
PDB id:
1l8c
Name: Gene regulation
Title: Structural basis for hif-1alpha/cbp recognition in the cellular hypoxic response
Structure: Creb-binding protein. Chain: a. Fragment: taz1 (transcription activation zinc finger) domain, residues 345-439. Engineered: yes. Hypoxia-inducible factor 1 alpha. Chain: b. Fragment: ctad (c-terminal activation) domain, residues 776-826. Synonym: hif-1 alpha, arnt interacting protein, member of pas protein
Source: Mus musculus. House mouse. Organism_taxid: 10090. Expressed in: escherichia coli. Expression_system_taxid: 562. Homo sapiens. Human. Organism_taxid: 9606. Expression_system_taxid: 562
NMR struc: 20 models
Authors: S.A.Dames,M.Martinez-Yamout,R.N.De Guzman,H.J.Dyson,P.E.Wright
Key ref:
S.A.Dames et al. (2002). Structural basis for Hif-1 alpha /CBP recognition in the cellular hypoxic response. Proc Natl Acad Sci U S A, 99, 5271-5276. PubMed id: 11959977 DOI: 10.1073/pnas.082121399
Date:
19-Mar-02     Release date:   10-Apr-02    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P45481  (CBP_MOUSE) -  Histone lysine acetyltransferase CREBBP from Mus musculus
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		2441 a.a.
95 a.a.
Protein chain
Pfam   ArchSchema ?
Q16665  (HIF1A_HUMAN) -  Hypoxia-inducible factor 1-alpha from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		826 a.a.
51 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 1: Chain A: E.C.2.3.1.-  - ?????
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
   Enzyme class 2: Chain A: E.C.2.3.1.48  - histone acetyltransferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: L-lysyl-[protein] + acetyl-CoA = N6-acetyl-L-lysyl-[protein] + CoA + H+
L-lysyl-[protein]
 + acetyl-CoA
 = N(6)-acetyl-L-lysyl-[protein]
 + CoA
 + H(+)
   Enzyme class 3: Chain B: E.C.?
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    Added reference    
 
 
DOI no: 10.1073/pnas.082121399 Proc Natl Acad Sci U S A 99:5271-5276 (2002)
PubMed id: 11959977  
 
 
Structural basis for Hif-1 alpha /CBP recognition in the cellular hypoxic response.
S.A.Dames, M.Martinez-Yamout, R.N.De Guzman, H.J.Dyson, P.E.Wright.
 
  ABSTRACT  
 
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.
 
  Selected figure(s)  
 
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). 		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.
 
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20882602 S.Kushal, H.Wang, C.F.László, L.Z.Szábo, and B.Z.Olenyuk (2011).
Inhibition of hypoxia-inducible transcription factor complex with designed epipolythiodiketopiperazine.
  Biopolymers, 95, 8.  
21335549 Y.M.Tian, K.K.Yeoh, M.K.Lee, T.Eriksson, B.M.Kessler, H.B.Kramer, M.J.Edelmann, C.Willam, C.W.Pugh, C.J.Schofield, and P.J.Ratcliffe (2011).
Differential sensitivity of hypoxia inducible factor hydroxylation sites to hypoxia and hydroxylase inhibitors.
  J Biol Chem, 286, 13041-13051.  
20100603 B.Xue, R.L.Dunbrack, R.W.Williams, A.K.Dunker, and V.N.Uversky (2010).
PONDR-FIT: a meta-predictor of intrinsically disordered amino acids.
  Biochim Biophys Acta, 1804, 996.  
19880525 J.L.Ruas, U.Berchner-Pfannschmidt, S.Malik, K.Gradin, J.Fandrey, R.G.Roeder, T.Pereira, and L.Poellinger (2010).
Complex regulation of the transactivation function of hypoxia-inducible factor-1 alpha by direct interaction with two distinct domains of the CREB-binding protein/p300.
  J Biol Chem, 285, 2601-2609.  
19926662 K.G.Pringle, K.L.Kind, A.N.Sferruzzi-Perri, J.G.Thompson, and C.T.Roberts (2010).
Beyond oxygen: complex regulation and activity of hypoxia inducible factors in pregnancy.
  Hum Reprod Update, 16, 415-431.  
20821791 L.K.Henchey, J.R.Porter, I.Ghosh, and P.S.Arora (2010).
High specificity in protein recognition by hydrogen-bond-surrogate α-helices: selective inhibition of the p53/MDM2 complex.
  Chembiochem, 11, 2104-2107.  
20041650 L.K.Henchey, S.Kushal, R.Dubey, R.N.Chapman, B.Z.Olenyuk, and P.S.Arora (2010).
Inhibition of hypoxia inducible factor 1-transcription coactivator interaction by a hydrogen bond surrogate alpha-helix.
  J Am Chem Soc, 132, 941-943.  
20616042 M.Kjaergaard, K.Teilum, and F.M.Poulsen (2010).
Conformational selection in the molten globule state of the nuclear coactivator binding domain of CBP.
  Proc Natl Acad Sci U S A, 107, 12535-12540.
PDB code: 2kkj
20534573 M.L.Nelson, H.S.Kang, G.M.Lee, A.G.Blaszczak, D.K.Lau, L.P.McIntosh, and B.J.Graves (2010).
Ras signaling requires dynamic properties of Ets1 for phosphorylation-enhanced binding to coactivator CBP.
  Proc Natl Acad Sci U S A, 107, 10026-10031.
PDB code: 2kmd
19755960 Y.Guan, K.R.Reddy, Q.Zhu, Y.Li, K.Lee, P.Weerasinghe, J.Prchal, G.L.Semenza, and N.Jing (2010).
G-rich oligonucleotides inhibit HIF-1alpha and HIF-2alpha and block tumor growth.
  Mol Ther, 18, 188-197.  
19162471 D.Eliezer (2009).
Biophysical characterization of intrinsically disordered proteins.
  Curr Opin Struct Biol, 19, 23-30.  
19179334 D.F.Estrada, D.M.Boudreaux, D.Zhong, S.C.St Jeor, and R.N.De Guzman (2009).
The Hantavirus Glycoprotein G1 Tail Contains Dual CCHC-type Classical Zinc Fingers.
  J Biol Chem, 284, 8654-8660.
PDB code: 2k9h
19357310 J.C.Ferreon, C.W.Lee, M.Arai, M.A.Martinez-Yamout, H.J.Dyson, and P.E.Wright (2009).
Cooperative regulation of p53 by modulation of ternary complex formation with CBP/p300 and HDM2.
  Proc Natl Acad Sci U S A, 106, 6591-6596.  
19214187 J.M.Wojciak, M.A.Martinez-Yamout, H.J.Dyson, and P.E.Wright (2009).
Structural basis for recruitment of CBP/p300 coactivators by STAT1 and STAT2 transactivation domains.
  EMBO J, 28, 948-958.
PDB codes: 2ka4 2ka6
20000859 K.M.Block, H.Wang, L.Z.Szabó, N.W.Polaske, L.K.Henchey, R.Dubey, S.Kushal, C.F.László, J.Makhoul, Z.Song, E.J.Meuillet, and B.Z.Olenyuk (2009).
Direct inhibition of hypoxia-inducible transcription factor complex with designed dimeric epidithiodiketopiperazine.
  J Am Chem Soc, 131, 18078-18088.  
19589782 K.M.Cook, S.T.Hilton, J.Mecinovic, W.B.Motherwell, W.D.Figg, and C.J.Schofield (2009).
Epidithiodiketopiperazines block the interaction between hypoxia-inducible factor-1alpha (HIF-1alpha) and p300 by a zinc ejection mechanism.
  J Biol Chem, 284, 26831-26838.  
19081931 L.Kelly, M.A.McDonough, M.L.Coleman, P.J.Ratcliffe, and C.J.Schofield (2009).
Asparagine beta-hydroxylation stabilizes the ankyrin repeat domain fold.
  Mol Biosyst, 5, 52-58.
PDB codes: 2zgd 2zgg
19845602 M.E.Cockman, J.D.Webb, and P.J.Ratcliffe (2009).
FIH-dependent asparaginyl hydroxylation of ankyrin repeat domain-containing proteins.
  Ann N Y Acad Sci, 1177, 9.  
19401150 S.E.Wilkins, J.Hyvärinen, J.Chicher, J.J.Gorman, D.J.Peet, R.L.Bilton, and P.Koivunen (2009).
Differences in hydroxylation and binding of Notch and HIF-1alpha demonstrate substrate selectivity for factor inhibiting HIF-1 (FIH-1).
  Int J Biochem Cell Biol, 41, 1563-1571.  
19402914 S.Fukuchi, K.Homma, Y.Minezaki, T.Gojobori, and K.Nishikawa (2009).
Development of an accurate classification system of proteins into structured and unstructured regions that uncovers novel structural domains: its application to human transcription factors.
  BMC Struct Biol, 9, 26.  
18842833 W.Feng, F.Ye, W.Xue, Z.Zhou, and Y.J.Kang (2009).
Copper regulation of hypoxia-inducible factor-1 activity.
  Mol Pharmacol, 75, 174-182.  
19186072 Z.K.Otrock, H.A.Hatoum, A.H.Awada, R.S.Ishak, and A.I.Shamseddine (2009).
Hypoxia-inducible factor in cancer angiogenesis: structure, regulation and clinical perspectives.
  Crit Rev Oncol Hematol, 70, 93.  
18404207 A.G.Turjanski, J.S.Gutkind, R.B.Best, and G.Hummer (2008).
Binding-induced folding of a natively unstructured transcription factor.
  PLoS Comput Biol, 4, e1000060.  
18375543 A.J.Filiano, C.D.Bailey, J.Tucholski, S.Gundemir, and G.V.Johnson (2008).
Transglutaminase 2 protects against ischemic insult, interacts with HIF1beta, and attenuates HIF1 signaling.
  FASEB J, 22, 2662-2675.  
18295234 H.S.Kang, M.L.Nelson, C.D.Mackereth, M.Schärpf, B.J.Graves, and L.P.McIntosh (2008).
Identification and structural characterization of a CBP/p300-binding domain from the ETS family transcription factor GABP alpha.
  J Mol Biol, 377, 636-646.
PDB code: 2juo
18202699 K.Lisy, and D.J.Peet (2008).
Turn me on: regulating HIF transcriptional activity.
  Cell Death Differ, 15, 642-649.  
18054500 K.Sugase, M.A.Landes, P.E.Wright, and M.Martinez-Yamout (2008).
Overexpression of post-translationally modified peptides in Escherichia coli by co-expression with modifying enzymes.
  Protein Expr Purif, 57, 108-115.  
19008886 M.Fuxreiter, P.Tompa, I.Simon, V.N.Uversky, J.C.Hansen, and F.J.Asturias (2008).
Malleable machines take shape in eukaryotic transcriptional regulation.
  Nat Chem Biol, 4, 728-737.  
18568157 R.Chowdhury, A.Hardy, and C.J.Schofield (2008).
The human oxygen sensing machinery and its manipulation.
  Chem Soc Rev, 37, 1308-1319.  
18219320 T.Klimova, and N.S.Chandel (2008).
Mitochondrial complex III regulates hypoxic activation of HIF.
  Cell Death Differ, 15, 660-666.  
18830487 Y.H.Chen, L.M.Comeaux, S.J.Eyles, and M.J.Knapp (2008).
Auto-hydroxylation of FIH-1: an Fe(ii), alpha-ketoglutarate-dependent human hypoxia sensor.
  Chem Commun (Camb), (), 4768-4770.  
18458062 Y.Li, T.Kimura, R.W.Huyck, J.H.Laity, and G.K.Andrews (2008).
Zinc-induced formation of a coactivator complex containing the zinc-sensing transcription factor MTF-1, p300/CBP, and Sp1.
  Mol Cell Biol, 28, 4275-4284.  
18687679 Y.Wang, D.M.Boudreaux, D.F.Estrada, C.W.Egan, S.C.St Jeor, and R.N.De Guzman (2008).
NMR structure of the N-terminal coiled coil domain of the Andes hantavirus nucleocapsid protein.
  J Biol Chem, 283, 28297-28304.
PDB code: 2k48
17301803 A.Ozer, and R.K.Bruick (2007).
Non-heme dioxygenases: cellular sensors and regulators jelly rolled into one?
  Nat Chem Biol, 3, 144-153.  
17438265 D.P.Teufel, S.M.Freund, M.Bycroft, and A.R.Fersht (2007).
Four domains of p300 each bind tightly to a sequence spanning both transactivation subdomains of p53.
  Proc Natl Acad Sci U S A, 104, 7009-7014.  
17562787 E.L.Bell, T.A.Klimova, J.Eisenbart, C.T.Moraes, M.P.Murphy, G.R.Budinger, and N.S.Chandel (2007).
The Qo site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production.
  J Cell Biol, 177, 1029-1036.  
17935336 K.Sugase, J.C.Lansing, H.J.Dyson, and P.E.Wright (2007).
Tailoring relaxation dispersion experiments for fast-associating protein complexes.
  J Am Chem Soc, 129, 13406-13407.  
17220275 Q.Yan, S.Bartz, M.Mao, L.Li, and W.G.Kaelin (2007).
The hypoxia-inducible factor 2alpha N-terminal and C-terminal transactivation domains cooperate to promote renal tumorigenesis in vivo.
  Mol Cell Biol, 27, 2092-2102.  
17081102 A.Huwiler, and J.Pfeilschifter (2006).
Hypoxia and lipid signaling.
  Biol Chem, 387, 1321-1328.  
16412252 C.Hebert, K.Norris, P.Parashar, R.A.Ord, N.G.Nikitakis, and J.J.Sauk (2006).
Hypoxia-inducible factor-1alpha polymorphisms and TSC1/2 mutations are complementary in head and neck cancers.
  Mol Cancer, 5, 3.  
16842166 D.G.Nagle, and Y.D.Zhou (2006).
Natural product-derived small molecule activators of hypoxia-inducible factor-1 (HIF-1).
  Curr Pharm Des, 12, 2673-2688.  
16635809 D.Jung, Y.Choi, and M.Uesugi (2006).
Small organic molecules that modulate gene transcription.
  Drug Discov Today, 11, 452-457.  
16543236 D.M.Fath, X.Kong, D.Liang, Z.Lin, A.Chou, Y.Jiang, J.Fang, J.Caro, and N.Sang (2006).
Histone deacetylase inhibitors repress the transactivation potential of hypoxia-inducible factors independently of direct acetylation of HIF-alpha.
  J Biol Chem, 281, 13612-13619.  
16548775 G.L.Semenza (2006).
Development of novel therapeutic strategies that target HIF-1.
  Expert Opin Ther Targets, 10, 267-280.  
16732694 J.Lu, M.Machius, I.Dulubova, H.Dai, T.C.Südhof, D.R.Tomchick, and J.Rizo (2006).
Structural basis for a Munc13-1 homodimer to Munc13-1/RIM heterodimer switch.
  PLoS Biol, 4, e192.
PDB codes: 2cjs 2cjt
16925945 M.Ohh (2006).
Ubiquitin pathway in VHL cancer syndrome.
  Neoplasia, 8, 623-629.  
16428465 S.Kajimura, K.Aida, and C.Duan (2006).
Understanding hypoxia-induced gene expression in early development: in vitro and in vivo analysis of hypoxia-inducible factor 1-regulated zebra fish insulin-like growth factor binding protein 1 gene expression.
  Mol Cell Biol, 26, 1142-1155.  
16847340 S.Kaluz, M.Kaluzová, and E.J.Stanbridge (2006).
Proteasomal inhibition attenuates transcriptional activity of hypoxia-inducible factor 1 (HIF-1) via specific effect on the HIF-1alpha C-terminal activation domain.
  Mol Cell Biol, 26, 5895-5907.  
16283145 D.C.Fry, and L.T.Vassilev (2005).
Targeting protein-protein interactions for cancer therapy.
  J Mol Med, 83, 955-963.  
16389310 D.E.Merry (2005).
Animal models of Kennedy disease.
  NeuroRx, 2, 471-479.  
15738986 H.J.Dyson, and P.E.Wright (2005).
Intrinsically unstructured proteins and their functions.
  Nat Rev Mol Cell Biol, 6, 197-208.  
15908239 J.L.Ruas, and L.Poellinger (2005).
Hypoxia-dependent activation of HIF into a transcriptional regulator.
  Semin Cell Dev Biol, 16, 514-522.  
16237459 L.H.Kasper, F.Boussouar, K.Boyd, W.Xu, M.Biesen, J.Rehg, T.A.Baudino, J.L.Cleveland, and P.K.Brindle (2005).
Two transactivation mechanisms cooperate for the bulk of HIF-1-responsive gene expression.
  EMBO J, 24, 3846-3858.  
15629713 N.Sánchez-Puig, D.B.Veprintsev, and A.R.Fersht (2005).
Binding of natively unfolded HIF-1alpha ODD domain to p53.
  Mol Cell, 17, 11-21.  
15800008 T.Gaber, R.Dziurla, R.Tripmacher, G.R.Burmester, and F.Buttgereit (2005).
Hypoxia inducible factor (HIF) in rheumatology: low O2! See what HIF can do!
  Ann Rheum Dis, 64, 971-980.  
16094605 V.N.Uversky, C.J.Oldfield, and A.K.Dunker (2005).
Showing your ID: intrinsic disorder as an ID for recognition, regulation and cell signaling.
  J Mol Recognit, 18, 343-384.  
15952883 W.G.Kaelin (2005).
Proline hydroxylation and gene expression.
  Annu Rev Biochem, 74, 115-128.  
15003169 B.L.Sopher, P.S.Thomas, M.A.LaFevre-Bernt, I.E.Holm, S.A.Wilke, C.B.Ware, L.W.Jin, R.T.Libby, L.M.Ellerby, and A.R.La Spada (2004).
Androgen receptor YAC transgenic mice recapitulate SBMA motor neuronopathy and implicate VEGF164 in the motor neuron degeneration.
  Neuron, 41, 687-699.  
15122348 C.J.Schofield, and P.J.Ratcliffe (2004).
Oxygen sensing by HIF hydroxylases.
  Nat Rev Mol Cell Biol, 5, 343-354.  
15341784 K.S.Hewitson, and C.J.Schofield (2004).
The HIF pathway as a therapeutic target.
  Drug Discov Today, 9, 704-711.  
15071503 M.Koshiji, Y.Kageyama, E.A.Pete, I.Horikawa, J.C.Barrett, and L.E.Huang (2004).
HIF-1alpha induces cell cycle arrest by functionally counteracting Myc.
  EMBO J, 23, 1949-1956.  
12603311 D.Lando, J.J.Gorman, M.L.Whitelaw, and D.J.Peet (2003).
Oxygen-dependent regulation of hypoxia-inducible factors by prolyl and asparaginyl hydroxylation.
  Eur J Biochem, 270, 781-790.  
13130303 G.L.Semenza (2003).
Targeting HIF-1 for cancer therapy.
  Nat Rev Cancer, 3, 721-732.  
  12639980 M.Safran, and W.G.Kaelin (2003).
HIF hydroxylation and the mammalian oxygen-sensing pathway.
  J Clin Invest, 111, 779-783.  
14668441 P.J.Erbel, P.B.Card, O.Karakuzu, R.K.Bruick, and K.H.Gardner (2003).
Structural basis for PAS domain heterodimerization in the basic helix--loop--helix-PAS transcription factor hypoxia-inducible factor.
  Proc Natl Acad Sci U S A, 100, 15504-15509.
PDB code: 1p97
12825087 S.Bhattacharya, and P.J.Ratcliffe (2003).
ExCITED about HIF.
  Nat Struct Biol, 10, 501-503.  
12778114 S.J.Freedman, Z.Y.Sun, A.L.Kung, D.S.France, G.Wagner, and M.J.Eck (2003).
Structural basis for negative regulation of hypoxia-inducible factor-1alpha by CITED2.
  Nat Struct Biol, 10, 504-512.
PDB code: 1p4q
12573436 W.Kim, and W.G.Kaelin (2003).
The von Hippel-Lindau tumor suppressor protein: new insights into oxygen sensing and cancer.
  Curr Opin Genet Dev, 13, 55-60.  
12147236 C.Z.Song, K.Keller, Y.Chen, K.Murata, and G.Stamatoyannopoulos (2002).
Transcription coactivator CBP has direct DNA binding activity and stimulates transcription factor DNA binding through small domains.
  Biochem Biophys Res Commun, 296, 118-124.  
12186981 G.L.Semenza (2002).
Physiology meets biophysics: visualizing the interaction of hypoxia-inducible factor 1 alpha with p300 and CBP.
  Proc Natl Acad Sci U S A, 99, 11570-11572.  
12209156 W.G.Kaelin (2002).
Molecular basis of the VHL hereditary cancer syndrome.
  Nat Rev Cancer, 2, 673-682.  
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.

 

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