PDBsum entry 1kv6

Gene regulation

PDB id: 1kv6

Contents

Protein chains

222 a.a. *

11 a.a. *

Ligands

HIS-LYS-ILE-LEU-HIS-ARG-LEU-LEU-GLN-GLU

Waters ×31

* Residue conservation analysis

PDB id:

1kv6

Name:

Gene regulation

Title:

X-ray structure of the orphan nuclear receptor err3 ligand-binding domain in the constitutively active conformation

Structure:

Estrogen-related receptor gamma. Chain: a, b. Fragment: ligand-binding domain. Synonym: err gamma-2. Nuclear receptor errg2. Estrogen-related receptor 3. Engineered: yes. Other_details: complex with a src1 coactivator peptide in the absence of ligand. Steroid receptor coactivator 1.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: nr3b3. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes. Other_details: this sequence occurs naturally in humans

Biol. unit:

Tetramer (from PQS)

Resolution:

2.70Å R-factor: 0.233 R-free: 0.267

Authors:

H.Greschik,J.-M.Wurtz,S.Sanglier,W.Bourguet,A.Van Dorsselaer,D.Moras, J.-P.Renaud,Structural Proteomics In Europe (Spine)

Key ref:

H.Greschik et al. (2002). Structural and functional evidence for ligand-independent transcriptional activation by the estrogen-related receptor 3. Mol Cell, 9, 303-313. PubMed id: 11864604 DOI: 10.1016/S1097-2765(02)00444-6

Date:

25-Jan-02 Release date: 25-Jan-03

Protein chains

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

Seq: 458 a.a.

Struc: 222 a.a.

Protein chain

Q15788  (NCOA1_HUMAN) -  Nuclear receptor coactivator 1 from Homo sapiens

Seq: 1441 a.a.

Struc: 11 a.a.

Enzyme reactions

• Enzyme class: Chain D: E.C.2.3.1.48 - histone acetyltransferase.
• Reaction: L-lysyl-[protein] + acetyl-CoA = N₆-acetyl-L-lysyl-[protein] + CoA + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1016/S1097-2765(02)00444-6

Mol Cell 9:303-313 (2002)

PubMed id: 11864604

Structural and functional evidence for ligand-independent transcriptional activation by the estrogen-related receptor 3.

H.Greschik, J.M.Wurtz, S.Sanglier, W.Bourguet, A.van Dorsselaer, D.Moras, J.P.Renaud.

ABSTRACT

The crystal structure of the ligand binding domain (LBD) of the estrogen-related receptor 3 (ERR3) complexed with a steroid receptor coactivator-1 (SRC-1) peptide reveals a transcriptionally active conformation in absence of any ligand. The structure explains why estradiol does not bind ERRs with significant affinity. Docking of the previously reported ERR antagonists, diethylstilbestrol and 4-hydroxytamoxifen, requires structural rearrangements enlarging the ligand binding pocket that can only be accommodated with an antagonist LBD conformation. Mutant receptors in which the ligand binding cavity is filled up by bulkier side chains still interact with SRC-1 in vitro and are transcriptionally active in vivo, but are no longer efficiently inactivated by diethylstilbestrol or 4-hydroxytamoxifen. These results provide structural and functional evidence for ligand-independent transcriptional activation by ERR3.

Selected figure(s)

Figure 2.
Figure 2. Schematic Representation of the Ligand binding Pocket of the ERR3 LBD(A) In the crystal structure, the positions of all shown side chains are well defined, with the exception of that of E275, which exhibits high temperature factors. All atoms are colored according to the following code: carbon, gray; oxygen, red; nitrogen, blue; sulfur, yellow.(B) View as in (A) with E2 docked into the empty ligand binding cavity of ERR3. The position of E2 results from the superposition of the ERR3 LBD and the ERα LBD/E2 complex. Steric interference with the D-ring of E2 is mainly due to the presence of F435 (L525 in hERα) and L345 (I424 in hERα) in ERR3.(C) Schematic comparison of amino acid residues that form the ligand binding pocket in hERR3 with the corresponding residues of hERR2, hERR1, and hERα. Residues that are conserved among all four receptors are depicted in yellow, and those conserved among the ERR isotypes are colored in blue. Amino acids of hERα that according to our modeling studies allow the binding of E2 to ERs but not to ERRs are highlighted in red. Important isotype-specific amino acid differences are colored in green.

Figure 4.
Figure 4. In Vitro Interaction Between Wild-Type or Mutant LBDs of ERR3 and the RID of SRC-1Two micrograms (about 70 pmol) of partially purified His-tagged ERR3 LBD was preincubated for 10 min on ice with 4 μg (about 100 pmol) of GST-tagged SRC-1 RID or GST in the absence (A) or in the presence ([B] and [C]) of 10^−4 M 4-OHT or 10^−4 M DES. Complexes were separated on native polyacrylamide gradient gels.

The above figures are reprinted by permission from Cell Press: Mol Cell (2002, 9, 303-313) copyright 2002.

Figures were selected by the author.