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PDBsum entry 1xc5

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Transcription corepressor PDB id
1xc5
Jmol
Contents
Protein chain
68 a.a. *
* Residue conservation analysis
PDB id:
1xc5
Name: Transcription corepressor
Title: Solution structure of the smrt deacetylase activation domain
Structure: Nuclear receptor corepressor 2. Chain: a. Fragment: deacetylase activation domain (residues 410-480). Synonym: smrt, n-cor2, silencing mediator of retinoic acid and thyroid hormone receptor, smrte, thyroid-, retinoic- acid-receptor-associated corepressor, t3 receptor- associating factor, trac, ctg repeat protein 26, smap270. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
NMR struc: 28 models
Authors: A.Codina,J.D.Love,Y.Li,M.A.Lazar,D.Neuhaus,J.W.R.Schwabe
Key ref:
A.Codina et al. (2005). Structural insights into the interaction and activation of histone deacetylase 3 by nuclear receptor corepressors. Proc Natl Acad Sci U S A, 102, 6009-6014. PubMed id: 15837933 DOI: 10.1073/pnas.0500299102
Date:
01-Sep-04     Release date:   03-May-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q9Y618  (NCOR2_HUMAN) -  Nuclear receptor corepressor 2
Seq:
Struc:
 
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Seq:
Struc:
2525 a.a.
68 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biochemical function     chromatin binding     2 terms  

 

 
DOI no: 10.1073/pnas.0500299102 Proc Natl Acad Sci U S A 102:6009-6014 (2005)
PubMed id: 15837933  
 
 
Structural insights into the interaction and activation of histone deacetylase 3 by nuclear receptor corepressors.
A.Codina, J.D.Love, Y.Li, M.A.Lazar, D.Neuhaus, J.W.Schwabe.
 
  ABSTRACT  
 
SMRT (silencing mediator of retinoid acid and thyroid hormone receptor) and NCoR (nuclear receptor corepressor) are transcriptional corepressors that play an essential role in the regulation of development and metabolism. This role is achieved, in part, through the recruitment of a key histone deacetylase (HDAC3), which is itself indispensable for cell viability. The assembly of HDAC3 with the deacetylase activation domain (DAD) of SMRT and NCoR is required for activation of the otherwise inert deacetylase. The DAD comprises an N-terminal DAD-specific motif and a C-terminal SANT (SWI3/ADA2/NCoR/TFIIIB)-like domain. We report here the solution structure of the DAD from SMRT, which reveals a four-helical structure. The DAD differs from the SANT (and MYB) domains in that (i) it has an additional N-terminal helix and (ii) there is a notable hydrophobic groove on the surface of the domain. Structure-guided mutagenesis, combined with interaction assays, showed that residues in the vicinity of the hydrophobic groove are required for interaction with (and hence activation of) HDAC3. Importantly, one surface-exposed lysine is required for activation of HDAC3, but not for interaction. This lysine may play a uniquely important role in the mechanism of activating HDAC3.
 
  Selected figure(s)  
 
Figure 3.
Fig. 3. Comparison of the architecture (Top), electrostatic (Middle), and hydrophobic (Bottom) potential surfaces of the MYB, DAD, and SANT domains. Note the basic character of the DNA-binding surface of the MYB domain and the rather acidic nature of the corresponding surface of the SANT domain. The DAD is also rather basic. Importantly, the wider angle of helix H3 in the DAD results in a groove between the amino terminus of helix H3 and the loop between helices H1 and H2. This groove does not itself have any polar side chains, but acquires a basic charge caused by surrounding lysine residues. The hydrophobic potential of the surface [calculated by using GRID (35)] shows that whereas both the MYB and SANT domains have mostly polar surfaces, the groove in the DAD has a strikingly high hydrophobic potential, suggesting that it might mediate interactions with a nonpolar partner (36).
Figure 4.
Fig. 4. The interaction between SMRT DAD and HDAC3. (A) Effect of DAD mutations on the activation of HDAC3. The gray bars indicate the percentage of HDAC3 activity in a cotransfection assay. The numbers on the bars indicate the percentage of solvent exposure of that residue based on the lowest energy NMR structure. (B) Coimmunoprecipitation assay to monitor interaction between HDAC3 and the DAD mutants. Note that the interaction with HDAC3 mirrors the activation profile with the exception of the K449A mutation, which abolishes activation yet retains the ability to interact with HDAC3, showing that the two aspects are clearly separable. (C) Location of residues that perturb HDAC3 activity >50% (red) or <50% (green) in the structure of the DAD. Note that the residues that reduce HDAC3 activity cluster together on the surface of the DAD in the vicinity of a nonpolar groove.
 
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
23292142 S.H.You, H.W.Lim, Z.Sun, M.Broache, K.J.Won, and M.A.Lazar (2013).
Nuclear receptor co-repressors are required for the histone-deacetylase activity of HDAC3 in vivo.
  Nat Struct Mol Biol, 20, 182-187.  
22230954 P.J.Watson, L.Fairall, G.M.Santos, and J.W.Schwabe (2012).
Structure of HDAC3 bound to co-repressor and inositol tetraphosphate.
  Nature, 481, 335-340.
PDB code: 4a69
21240272 J.Oberoi, L.Fairall, P.J.Watson, J.C.Yang, Z.Czimmerer, T.Kampmann, B.T.Goult, J.A.Greenwood, J.T.Gooch, B.C.Kallenberger, L.Nagy, D.Neuhaus, and J.W.Schwabe (2011).
Structural basis for the assembly of the SMRT/NCoR core transcriptional repression machinery.
  Nat Struct Mol Biol, 18, 177-184.
PDB codes: 2l5g 2xtc 2xtd 2xte
20181716 M.L.Powell, J.A.Smith, M.E.Sowa, J.W.Harper, T.Iftner, F.Stubenrauch, and P.M.Howley (2010).
NCoR1 mediates papillomavirus E8;E2C transcriptional repression.
  J Virol, 84, 4451-4460.  
21075309 S.Bhaskara, S.K.Knutson, G.Jiang, M.B.Chandrasekharan, A.J.Wilson, S.Zheng, A.Yenamandra, K.Locke, J.L.Yuan, A.R.Bonine-Summers, C.E.Wells, J.F.Kaiser, M.K.Washington, Z.Zhao, F.F.Wagner, Z.W.Sun, F.Xia, E.B.Holson, D.Khabele, and S.W.Hiebert (2010).
Hdac3 is essential for the maintenance of chromatin structure and genome stability.
  Cancer Cell, 18, 436-447.  
20087432 I.J.McEwan, and A.M.Nardulli (2009).
Nuclear hormone receptor architecture - form and dynamics: The 2009 FASEB Summer Conference on Dynamic Structure of the Nuclear Hormone Receptors.
  Nucl Recept Signal, 7, e011.  
18632985 A.J.Wilson, D.S.Byun, S.Nasser, L.B.Murray, K.Ayyanar, D.Arango, M.Figueroa, A.Melnick, G.D.Kao, L.H.Augenlicht, and J.M.Mariadason (2008).
HDAC4 promotes growth of colon cancer cells via repression of p21.
  Mol Biol Cell, 19, 4062-4075.  
18309295 D.Qi, M.Bergman, H.Aihara, Y.Nibu, and M.Mannervik (2008).
Drosophila Ebi mediates Snail-dependent transcriptional repression through HDAC3-induced histone deacetylation.
  EMBO J, 27, 898-909.  
18840288 E.R.Ko, D.Ko, C.Chen, and J.S.Lipsick (2008).
A conserved acidic patch in the Myb domain is required for activation of an endogenous target gene and for chromatin binding.
  Mol Cancer, 7, 77.  
18710950 K.R.Badri, Y.Zhou, U.Dhru, S.Aramgam, and L.Schuger (2008).
Effects of the SANT domain of tension-induced/inhibited proteins (TIPs), novel partners of the histone acetyltransferase p300, on p300 activity and TIP-6-induced adipogenesis.
  Mol Cell Biol, 28, 6358-6372.  
17999998 M.Malinen, A.Saramäki, A.Ropponen, T.Degenhardt, S.Väisänen, and C.Carlberg (2008).
Distinct HDACs regulate the transcriptional response of human cyclin-dependent kinase inhibitor genes to Trichostatin A and 1alpha,25-dihydroxyvitamin D3.
  Nucleic Acids Res, 36, 121-132.  
17694085 P.Karagianni, and J.Wong (2007).
HDAC3: taking the SMRT-N-CoRrect road to repression.
  Oncogene, 26, 5439-5449.  
17158926 S.Grégoire, L.Xiao, J.Nie, X.Zhang, M.Xu, J.Li, J.Wong, E.Seto, and X.J.Yang (2007).
Histone deacetylase 3 interacts with and deacetylates myocyte enhancer factor 2.
  Mol Cell Biol, 27, 1280-1295.  
16382138 J.E.Hoberg, A.E.Popko, C.S.Ramsey, and M.W.Mayo (2006).
IkappaB kinase alpha-mediated derepression of SMRT potentiates acetylation of RelA/p65 by p300.
  Mol Cell Biol, 26, 457-471.  
16481466 L.Wang, H.Rajan, J.L.Pitman, M.McKeown, and C.C.Tsai (2006).
Histone deacetylase-associating Atrophin proteins are nuclear receptor corepressors.
  Genes Dev, 20, 525-530.  
16434964 M.I.Tussié-Luna, L.Rozo, and A.L.Roy (2006).
Pro-proliferative function of the long isoform of PML-RARalpha involved in acute promyelocytic leukemia.
  Oncogene, 25, 3375-3386.  
16531230 N.Tochio, T.Umehara, S.Koshiba, M.Inoue, T.Yabuki, M.Aoki, E.Seki, S.Watanabe, Y.Tomo, M.Hanada, M.Ikari, M.Sato, T.Terada, T.Nagase, O.Ohara, M.Shirouzu, A.Tanaka, T.Kigawa, and S.Yokoyama (2006).
Solution structure of the SWIRM domain of human histone demethylase LSD1.
  Structure, 14, 457-468.
PDB code: 2com
16849648 R.Mankidy, D.V.Faller, R.Mabaera, C.H.Lowrey, M.S.Boosalis, G.L.White, S.A.Castaneda, and S.P.Perrine (2006).
Short-chain fatty acids induce gamma-globin gene expression by displacement of a HDAC3-NCoR repressor complex.
  Blood, 108, 3179-3186.  
16604171 M.Goodson, B.A.Jonas, and M.A.Privalsky (2005).
Corepressors: custom tailoring and alterations while you wait.
  Nucl Recept Signal, 3, e003.  
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.