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PDBsum entry 3cs8
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protein ligands Protein-protein interface(s) links
Nuclear protein PDB id
3cs8

 

 

 

 

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Contents
Protein chains
269 a.a. *
12 a.a. *
Ligands
SO4 ×4
BRL
Waters ×88
* Residue conservation analysis
PDB id:
3cs8
Name: Nuclear protein
Title: Structural and biochemical basis for the binding selectivity of pparg to pgc-1a
Structure: Peroxisome proliferator-activated receptor gamma. Chain: a. Fragment: lbd domain (unp residues 234-504). Synonym: ppar-gamma, nuclear receptor subfamily 1 group c member 3. Engineered: yes. Pgc-1alfa peptide. Chain: b. Synonym: ppar-gamma coactivator 1-alpha, ppargc-1-alpha, pgc-1-alpha, ligand effect modulator 6.
Source: Homo sapiens. Gene: ppargc1a, lem6, pgc1, pgc1a, ppargc1. Expressed in: escherichia coli. Synthetic: yes. Other_details: the peptide is chemically synthesized. It is found naturally in humans
Resolution:
2.30Å     R-factor:   0.227     R-free:   0.282
Authors: Y.Li,D.Martynowski
Key ref:
Y.Li et al. (2008). Structural and biochemical basis for the binding selectivity of peroxisome proliferator-activated receptor gamma to PGC-1alpha. J Biol Chem, 283, 19132-19139. PubMed id: 18469005 DOI: 10.1074/jbc.M802040200
Date:
09-Apr-08     Release date:   03-Jun-08    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P37231  (PPARG_HUMAN) -  Peroxisome proliferator-activated receptor gamma from Homo sapiens
Seq:
Struc: 		505 a.a.
269 a.a.*
Protein chain
Pfam   ArchSchema ?
Q9UBK2  (PRGC1_HUMAN) -  Peroxisome proliferator-activated receptor gamma coactivator 1-alpha from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		798 a.a.
12 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 4 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chains A, B: E.C.?
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

 

 
DOI no: 10.1074/jbc.M802040200 J Biol Chem 283:19132-19139 (2008)
PubMed id: 18469005  
 
 
Structural and biochemical basis for the binding selectivity of peroxisome proliferator-activated receptor gamma to PGC-1alpha.
Y.Li, A.Kovach, K.Suino-Powell, D.Martynowski, H.E.Xu.
 
  ABSTRACT  
 
The functional interaction between the peroxisome proliferator-activated receptor gamma (PPARgamma) and its coactivator PGC-1alpha is crucial for the normal physiology of PPARgamma and its pharmacological response to antidiabetic treatment with rosiglitazone. Here we report the crystal structure of the PPARgamma ligand-binding domain bound to rosiglitazone and to a large PGC-1alpha fragment that contains two LXXLL-related motifs. The structure reveals critical contacts mediated through the first LXXLL motif of PGC-1alpha and the PPARgamma coactivator binding site. Through a combination of biochemical and structural studies, we demonstrate that the first LXXLL motif is the most potent among all nuclear receptor coactivator motifs tested, and only this motif of the two LXXLL-related motifs in PGC-1alpha is capable of binding to PPARgamma. Our studies reveal that the strong interaction of PGC-1alpha and PPARgamma is mediated through both hydrophobic and specific polar interactions. Mutations within the context of the full-length PGC-1alpha indicate that the first PGC-1alpha motif is necessary and sufficient for PGC-1alpha to coactivate PPARgamma in the presence or absence of rosiglitazone. These results provide a molecular basis for specific recruitment and functional interplay between PPARgamma and PGC-1alpha in glucose homeostasis and adipocyte differentiation.
 
  Selected figure(s)  
 
Figure 3.
FIGURE 3. Purification and crystallization of the PPAR LBD complexed with a PGC-1 fragment. A, a schematic representation showing the PGC-1 protein and its two receptor-interacting motifs (ID1 and ID2). The PGC-1 fragment (101-220) that includes both ID1 and ID2 motifs was used in cocrystallization with PPAR . B, purification of the PPAR LBD and PGC-1 complex. The proteins of PPAR and PGC-1 were purified separately and complexed using excess PGC-1 in the presence of rosiglitazone. The PPAR ·PGC-1 complex and PGC-1 alone were separated by gel filtration. The complex was eluted in the first peak and collected and concentrated to 10 mg/ml for the crystallization trial. C, the protein complex samples shown on an SDS gel. The molecular mass markers are shown in the KD lane (kilodaltons). Lanes 1-9 are fractions from the gel filtration column corresponding to the two peaks in B, from left to right. D, crystals of the PPAR ·rosiglitazone·PGC-1 complex. 		Figure 6.
FIGURE 6. Molecular determinants of the PGC-1 /PPAR interactions. A and B, the docking mode of PGC-1 ID1 (yellow) on the surface of PPAR (coactivator binding site) is shown. The hydrophobic interaction is shown in A, and the specific intermolecular interaction is shown in B. C and D, the binding interface of PGC-1 /PPAR shows the specific intermolecular and intramolecular interactions. The PGC-1 is shown in green, the PPAR is in red, and the hydrogen bonds are shown as arrows.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2008, 283, 19132-19139) copyright 2008.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20732852 J.Li, A.Dai, R.Hu, L.Zhu, and S.Tan (2010).
Positive correlation between PPARgamma/PGC-1alpha and gamma-GCS in lungs of rats and patients with chronic obstructive pulmonary disease.
  Acta Biochim Biophys Sin (Shanghai), 42, 603-614.  
20723571 L.Jin, and Y.Li (2010).
Structural and functional insights into nuclear receptor signaling.
  Adv Drug Deliv Rev, 62, 1218-1226.  
  20814439 N.Viswakarma, Y.Jia, L.Bai, A.Vluggens, J.Borensztajn, J.Xu, and J.K.Reddy (2010).
Coactivators in PPAR-Regulated Gene Expression.
  PPAR Res, 2010, 0.  
19746174 S.N.Lewis, J.Bassaganya-Riera, and D.R.Bevan (2010).
Virtual Screening as a Technique for PPAR Modulator Discovery.
  PPAR Res, 2010, 861238.  
20086010 X.E.Zhou, K.M.Suino-Powell, J.Li, Y.He, J.P.Mackeigan, K.Melcher, E.L.Yong, and H.E.Xu (2010).
Identification of SRC3/AIB1 as a preferred coactivator for hormone-activated androgen receptor.
  J Biol Chem, 285, 9161-9171.
PDB codes: 3l3x 3l3z
19995608 X.E.Zhou, K.Suino-Powell, P.L.Ludidi, D.P.McDonnell, and H.E.Xu (2010).
Expression, purification and primary crystallographic study of human androgen receptor in complex with DNA and coactivator motifs.
  Protein Expr Purif, 71, 21-27.  
19846556 G.B.Rha, G.Wu, S.E.Shoelson, and Y.I.Chi (2009).
Multiple binding modes between HNF4alpha and the LXXLL motifs of PGC-1alpha lead to full activation.
  J Biol Chem, 284, 35165-35176.
PDB code: 3fs1
19898420 K.Melcher, L.M.Ng, X.E.Zhou, F.F.Soon, Y.Xu, K.M.Suino-Powell, S.Y.Park, J.J.Weiner, H.Fujii, V.Chinnusamy, A.Kovach, J.Li, Y.Wang, J.Li, F.C.Peterson, D.R.Jensen, E.L.Yong, B.F.Volkman, S.R.Cutler, J.K.Zhu, and H.E.Xu (2009).
A gate-latch-lock mechanism for hormone signalling by abscisic acid receptors.
  Nature, 462, 602-608.  
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 codes are shown on the right.

 

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