PDBsum entry 2qpy

DNA binding protein

PDB id: 2qpy

Contents

Protein chain

248 a.a. *

Ligands

LEU-LEU-ARG-TYR-LEU-LEU-ASP-LYS-ASP-ASP

DHT

4HY

Waters ×24

* Residue conservation analysis

PDB id:

2qpy

Name:

DNA binding protein

Title:

Ar lbd with small molecule

Structure:

Androgen receptor. Chain: a. Synonym: dihydrotestosterone receptor. Engineered: yes. Coactivator peptide. Chain: b. Engineered: yes

Source:

Mus musculus. House mouse. Organism_taxid: 10090. Gene: ar, nr3c4. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Synthetic construct. Organism_taxid: 32630

Resolution:

2.50Å R-factor: 0.269 R-free: 0.269

Authors:

E.Estebanez-Perpina,R.Fletterick

Key ref:

E.Estébanez-Perpiñá et al. (2007). A surface on the androgen receptor that allosterically regulates coactivator binding. Proc Natl Acad Sci U S A, 104, 16074-16079. PubMed id: 17911242 DOI: 10.1073/pnas.0708036104

Date:

25-Jul-07 Release date: 25-Sep-07

Protein chain

P19091  (ANDR_MOUSE) -  Androgen receptor from Mus musculus

Seq: 899 a.a.

Struc: 248 a.a.

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1073/pnas.0708036104

Proc Natl Acad Sci U S A 104:16074-16079 (2007)

PubMed id: 17911242

A surface on the androgen receptor that allosterically regulates coactivator binding.

E.Estébanez-Perpiñá, L.A.Arnold, A.A.Arnold, P.Nguyen, E.D.Rodrigues, E.Mar, R.Bateman, P.Pallai, K.M.Shokat, J.D.Baxter, R.K.Guy, P.Webb, R.J.Fletterick.

ABSTRACT

Current approaches to inhibit nuclear receptor (NR) activity target the hormone binding pocket but face limitations. We have proposed that inhibitors, which bind to nuclear receptor surfaces that mediate assembly of the receptor's binding partners, might overcome some of these limitations. The androgen receptor (AR) plays a central role in prostate cancer, but conventional inhibitors lose effectiveness as cancer treatments because anti-androgen resistance usually develops. We conducted functional and x-ray screens to identify compounds that bind the AR surface and block binding of coactivators for AR activation function 2 (AF-2). Four compounds that block coactivator binding in solution with IC(50) approximately 50 microM and inhibit AF-2 activity in cells were detected: three nonsteroidal antiinflammatory drugs and the thyroid hormone 3,3',5-triiodothyroacetic acid. Although visualization of compounds at the AR surface reveals weak binding at AF-2, the most potent inhibitors bind preferentially to a previously unknown regulatory surface cleft termed binding function (BF)-3, which is a known target for mutations in prostate cancer and androgen insensitivity syndrome. X-ray structural analysis reveals that 3,3',5-triiodothyroacetic acid binding to BF-3 remodels the adjacent interaction site AF-2 to weaken coactivator binding. Mutation of residues that form BF-3 inhibits AR function and AR AF-2 activity. We propose that BF-3 is a previously unrecognized allosteric regulatory site needed for AR activity in vivo and a possible pharmaceutical target.

Selected figure(s)

Figure 3.
AF-2 and BF-3. (A) Schematic of AR LBD showing location of DHT, key AF-2 helices 3, 5, and 12, and H1. (B) Space-filling model showing residues in AF-2 (cyan) and BF-3 (red). (C) As in B, rotated 90° to reveal BF-3.

Figure 4.
Interactions at the AR LBD surface. (A–C). BF-3 including Glu-829, Asn-833, Arg-840, Phe-673, and Tyr-834 is highlighted by dots and divided into two subpockets that accommodate Triac and FLF phenolic rings. Basic residues are in blue, and acidic residues are in red. Shown are close-ups of interactions with Triac (A) and FLF (B) as yellow stick models. (C) Superimposed Triac (yellow) plus FLF (dark blue). (D–F) AF-2 lined by Met-734, Lys-720, Glu-897, and Met-894 with subsites (S1–S3) highlighted by dots. Basic residues are in blue, acidic residues are in red, and Met is in yellow. D and E show close-ups of Triac and RB1, respectively. (F) Superimposed Triac (blue) plus RB1 (orange). Triac interacts with S1 and the area between S2 and S3 whereas RB1 interacts with S1 and S3.

Figures were selected by an automated process.