PDBsum entry 2gpp

Transcription

PDB id: 2gpp

Contents

Protein chains

225 a.a. *

11 a.a. *

13 a.a. *

Ligands

1BA

Waters ×25

* Residue conservation analysis

PDB id:

2gpp

Name:

Transcription

Title:

Estrogen related receptor-gamma ligand binding domain complexed with a rip140 peptide and synthetic ligand gsk4716

Structure:

Estrogen-related receptor gamma. Chain: a, b. Fragment: residues (229-458). Synonym: estrogen receptor-related protein 3, err gamma-2. Engineered: yes. Nuclear receptor-interacting protein 1. Chain: c, d. Fragment: residues (366-390). Synonym: nuclear factor rip140, receptor-interacting protein 140.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: esrrg. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes. Other_details: chemically synthesized. Occurs naturally in humans.

Biol. unit:

Tetramer (from PQS)

Resolution:

2.60Å R-factor: 0.233 R-free: 0.257

Authors:

L.Wang,W.J.Zuercher,T.G.Consler,M.H.Lambert,A.B.Miller,L.A.Osband- Miller,D.D.Mckee,T.M.Willson,R.T.Nolte

Key ref:

L.Wang et al. (2006). X-ray crystal structures of the estrogen-related receptor-gamma ligand binding domain in three functional states reveal the molecular basis of small molecule regulation. J Biol Chem, 281, 37773-37781. PubMed id: 16990259 DOI: 10.1074/jbc.M608410200

Date:

18-Apr-06 Release date: 26-Sep-06

Protein chains

P62508  (ERR3_HUMAN) -  Estrogen-related receptor gamma from Homo sapiens

Seq: 458 a.a.

Struc: 225 a.a.

Protein chain

P48552  (NRIP1_HUMAN) -  Nuclear receptor-interacting protein 1 from Homo sapiens

Seq: 1158 a.a.

Struc: 11 a.a.

Protein chain

P48552  (NRIP1_HUMAN) -  Nuclear receptor-interacting protein 1 from Homo sapiens

Seq: 1158 a.a.

Struc: 13 a.a.

Enzyme reactions

• Enzyme class: Chains A, B, C, D: E.C.?

DOI no: 10.1074/jbc.M608410200

J Biol Chem 281:37773-37781 (2006)

PubMed id: 16990259

X-ray crystal structures of the estrogen-related receptor-gamma ligand binding domain in three functional states reveal the molecular basis of small molecule regulation.

L.Wang, W.J.Zuercher, T.G.Consler, M.H.Lambert, A.B.Miller, L.A.Orband-Miller, D.D.McKee, T.M.Willson, R.T.Nolte.

ABSTRACT

X-ray crystal structures of the ligand binding domain (LBD) of the estrogen-related receptor-gamma (ERRgamma) were determined that describe this receptor in three distinct states: unliganded, inverse agonist bound, and agonist bound. Two structures were solved for the unliganded state, the ERRgamma LBD alone, and in complex with a coregulator peptide representing a portion of receptor interacting protein 140 (RIP140). No significant differences were seen between these structures that both exhibited the conformation of ERRgamma seen in studies with other coactivators. Two structures were obtained describing the inverse agonist-bound state, the ERRgamma LBD with 4-hydroxytamoxifen (4-OHT), and the ERRgamma LBD with 4-OHT and a peptide representing a portion of the silencing mediator of retinoid and thyroid hormone action protein (SMRT). The 4-OHT structure was similar to other reported inverse agonist bound structures, showing reorientation of phenylalanine 435 and a displacement of the AF-2 helix relative to the unliganded structures with little other rearrangement occurring. No significant changes to the LBD appear to be induced by peptide binding with the addition of the SMRT peptide to the ERRgamma plus 4-OHT complex. The observed agonist-bound state contains the ERRgamma LBD, a ligand (GSK4716), and the RIP140 peptide and reveals an unexpected rearrangement of the phenol-binding residues. Thermal stability studies show that agonist binding leads to global stabilization of the ligand binding domain. In contrast to the conventional mechanism of nuclear receptor ligand activation, activation of ERRgamma by GSK4716 does not appear to involve a major rearrangement or significant stabilization of the C-terminal helix.

Selected figure(s)

Figure 4.
FIGURE 4. ERR ·4-OHT·SMRT complex. The tetrameric assembly containing four of the six molecules in the asymmetric unit is shown. A ribbon representation of the ERR monomers is shown with each monomer shown with a distinct color: yellow, molecule A; magenta, molecule B; blue, molecule C; and green, molecule D. The ligand is depicted as a stick figure with orange carbon atoms. Residues 319-330 of the SMRT peptide are depicted as cyan ribbons with peptide chain G binding ERR chain A and peptide chain H binding ERR chain B. The remaining two molecules in the asymmetric unit form a similar tetramer with symmetrically related copies of themselves around a crystallographic 2-fold axis.

Figure 7.
FIGURE 7. Plot of ligand interactions in the ERR ·GSK4716·RIP140 complex. Hydrogen bonds involving the ligand are shown in red, with distances denoted in angstroms. The ligand hydrogen bonds directly to two residues, the side chain of Asp-328 and the back bone carbonyl of Tyr-327. Indirect hydrogen bonds to the ligand exist through two waters to the side chain of Arg-316 and the main chain of Leu-309. Residues denoted in blue are >4.0 Å from the ligand.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2006, 281, 37773-37781) copyright 2006.

Figures were selected by an automated process.