An evolving understanding of nuclear receptor coregulator proteins

  1. John W R Schwabe
  1. Henry Wellcome Laboratories of Structural Biology, Department of Biochemistry, University of Leicester, Leicester LE1 9HN, UK
  1. Correspondence should be addressed to J W R Schwabe; Email: john.schwabe{at}
  1. Figure 1

    Coregulator complexes are recruited to the genome through DNA-binding transcription factors such as nuclear receptors. (A) Cartoon to illustrate the recruitment of coactivator complex to genes by liganded nuclear receptors, resulting in the acetylation of histone tails and an increase in the rate of transcription. (B) Nuclear receptors recruit corepressor complexes in the absence of ligand, resulting in the deacetylation of histone tails and decrease in the rate of transcription. (C) Crystal structure of PPARγ (light blue) and RXRα (yellow) heterodimer bound to DNA with an NCOA2 peptide (green). Ligands rosiglitazone (for PPARγ and 9-cis retinoic acid (for RXRα are shown as purple sticks). Zinc atoms are shown as grey spheres (PDB code 3DZY (Chandra et al. 2008)). (D) Structure of PPARγ LBD (light blue) with the ligand rosiglitazone (pink) bound to a peptide from the SRC1 coactivator (green) (PDB code 2PRG (Nolte et al. 1998)). (E) Structure of PPARα LBD (light blue) with the antagonist GW6471 (pink) bound to a peptide from the SMRT corepressor (red) (PDB code 1KKQ (Xu et al. 2002)). Helix 12 is highlighted in yellow in both (D and E).

  2. Figure 2

    Crystal structures of coregulator proteins possessing enzymatic activity with schematic representations of their cognate complexes. (A) The histone deacetylase HDAC1 bound to an MTA1 dimer, with sulphate molecules bound at the positively charged inositol phosphate-binding interface between the two proteins (PDB code 4BKX (Millard et al. 2013)). (B) The histone acetyltransferase p300 with the inhibitor Lys-CoA (PDB code 3BIY (Liu et al. 2008)). In all panels: enzymes are shown in green, accessory proteins in blue, metal ions in grey and histone tails/cofactors as pink spheres. (C) The arginine methytransferase PRMT5 in complex with the adaptor protein MEP50 with bound AdoMet analogue and H4 peptide (PDB code 4GQB (Antonysamy et al. 2012)). (D) The demethylase LSD1 with corepressor CoREST. A histone H3 peptide covalently attached to FAD is bound in the active site of LSD1 (PDB code 2UXN (Yang et al. 2007)). (E) The ATPase domain from CHD1 with a bound nucleotide (PDB code 3MWY (Hauk et al. 2010)).

  3. Figure 3

    Space filling representations of chromatin binding modules. (A) Histone H4 acetylated at Lys16 bound to bromodomain of GCN5 (grey) (PDB code 1E6I (Owen et al. 2000)). (B) Histone H3 methylated at Lys9 bound to chromodomain of HP1 (grey) (PDB code 1GUW (Nielsen et al. 2002)). (C) Histone H3 tri-methylated at Lys27 bound to the WD40 domain of EED (grey) (PDB code 3IIW (Margueron et al. 2009)). (D) Histone H4 tail (amino acids 16–41) bound to the WD40 domain of RBAP46 shown in grey (PDB code 3CFS (Murzina et al. 2008)). (E) WD40 domain of RCC1 (grey) bound to a nucleosome (DNA blue, H2A green, H2B yellow, H3 pink and H4 red) (PDB code 3MVD (Makde et al. 2010)). (F) BAH domain of SIR3 (grey) bound to a nucleosome (DNA blue, H2A green, H2B yellow, H3 pink and H4 red) (PDB code 3TU4 (Armache et al. 2011)).

  4. Figure 4

    Schematic domain structures of coregulator proteins (A) NCoR/SMRT and (B) SRC1 and p300/CBP. A number of selected interaction domains are colour coded with respect to the role of the domains in the assembled complex. Structures of these domains are shown with the various interacting partners (GPS2/SMRT and TBL1 (PDB codes 2L5G and 2XTC (Oberoi et al. 2011)), HDAC3/SMRT and IP4 (pink spheres) (PDB code 4A69 (Watson et al. 2012a)), SMRT–SANT2 (PDB code 2ltp), BCL6/SMRT (PDB code 1r2b (Ahmad et al. 2003)), STAT6/SRC1 (PDB code 1OJ5 (Razeto et al. 2004)), HIF1a/CBP (PDB code 1l8c (Dames et al. 2002)), p300 (PDB code 4bhw (Delvecchio et al. 2013)) and SRC1/CBP (PDB code 2c52 (Waters et al. 2006))).

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