PDBsum entry 2b1v

Hormone/growth factor receptor

PDB id: 2b1v

Contents

Protein chains

236 a.a. *

Ligands

LYS-ILE-LEU-HIS-ARG-LEU-LEU-GLN-ASP ×2

458 ×2

Waters ×91

* Residue conservation analysis

PDB id:

2b1v

Name:

Hormone/growth factor receptor

Title:

Human estrogen receptor alpha ligand-binding domain in complex with obcp-1m and a glucocorticoid receptor interacting protein 1 nr box ii peptide

Structure:

Estrogen receptor. Chain: a, b. Fragment: ligand binding domain. Synonym: er, estradiol receptor, er-alpha. Engineered: yes. Mutation: yes. Nuclear receptor coactivator 2. Chain: c, d. Fragment: residues 686 - 698.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: esr1, esr, nr3a1. 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:

1.80Å R-factor: 0.205 R-free: 0.238

Authors:

S.S.Rajan,R.W.Hsieh,S.K.Sharma,G.L.Greene

Key ref:

R.W.Hsieh et al. (2006). Identification of ligands with bicyclic scaffolds provides insights into mechanisms of estrogen receptor subtype selectivity. J Biol Chem, 281, 17909-17919. PubMed id: 16648639 DOI: 10.1074/jbc.M513684200

Date:

16-Sep-05 Release date: 09-May-06

Protein chains

P03372  (ESR1_HUMAN) -  Estrogen receptor from Homo sapiens

Seq: 595 a.a.

Struc: 236 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

DOI no: 10.1074/jbc.M513684200

J Biol Chem 281:17909-17919 (2006)

PubMed id: 16648639

Identification of ligands with bicyclic scaffolds provides insights into mechanisms of estrogen receptor subtype selectivity.

R.W.Hsieh, S.S.Rajan, S.K.Sharma, Y.Guo, E.R.DeSombre, M.Mrksich, G.L.Greene.

ABSTRACT

Estrogen receptors alpha (ERalpha) and beta (ERbeta) have distinct functions and differential expression in certain tissues. These differences have stimulated the search for subtype-selective ligands. Therapeutically, such ligands offer the potential to target specific tissues or pathways regulated by one receptor subtype without affecting the other. As reagents, they can be utilized to probe the physiological functions of the ER subtypes to provide information complementary to that obtained from knock-out animals. A fluorescence resonance energy transfer-based assay was used to screen a 10,000-compound chemical library for ER agonists. From the screen, we identified a family of ERbeta-selective agonists whose members contain bulky oxabicyclic scaffolds in place of the planar scaffolds common to most ER ligands. These agonists are 10-50-fold selective for ERbeta in competitive binding assays and up to 60-fold selective in transactivation assays. The weak uterotrophic activity of these ligands in immature rats and their ability to stimulate expression of an ERbeta regulated gene in human U2OS osteosarcoma cells provides more physiological evidence of their ERbeta-selective nature. To provide insight into the molecular mechanisms of their activity and selectivity, we determined the crystal structures of the ERalpha ligand-binding domain (LBD) and a peptide from the glucocorticoid receptor-interacting protein 1 (GRIP1) coactivator complexed with the ligands OBCP-3M, OBCP-2M, and OBCP-1M. These structures illustrate how the bicyclic scaffolds of these ligands are accommodated in the flexible ligand-binding pocket of ER. A comparison of these structures with existing ER structures suggests that the ERbeta selectivity of OBCP ligands can be attributed to a combination of their interactions with Met-336 in ERbeta and Met-421 in ERalpha. These bicyclic ligands show promise as lead compounds that can target ERbeta. In addition, our understanding of the molecular determinants of their subtype selectivity provides a useful starting point for developing other ER modulators belonging to this relatively new structural class.

Selected figure(s)

Figure 6.
FIGURE 6. ER ligand binding site. Shown are ball-and-stick renderings of the ligands OBCP-3M(MonA) (A), OBCP-3M(MonB) (B), OBCP-2M(MonB) (C) (only the C9-S diastereomer shown), and OBCP-1M (D), along with their interacting residues and corresponding F[o] – F[c] electron density omit maps contoured at 1.95 (OBCP-3M), 1.35 (OBCP-2M), and 1.80 (OBCP-1M). Hydrogen bonds are shown as dotted lines.

Figure 7.
FIGURE 7. Ligand binding mode of OBCP-3M. Monomer A of OBCP-3M-ER LBD-GRIP1 complex (dark gray) was superimposed on monomer B of the same complex (A) and with other ER structures complexed with E2 (Protein Data Bank code 1ERE) (B) and DES (Protein Data Bank code 3ERD) (C) (all light gray). Shown are the ball-and-stick diagrams of their ligand binding sites.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2006, 281, 17909-17919) copyright 2006.

Figures were selected by an automated process.