PDBsum entry 2q7l

Hormone

PDB id: 2q7l

Contents

Protein chains

247 a.a. *

13 a.a. *

Ligands

TES

GOL

Waters ×151

* Residue conservation analysis

PDB id:

2q7l

Name:

Hormone

Title:

The androgen receptor prostate cancer mutant h874y ligand binding domain bound with testosterone and a tif2 box3 coactivator peptide 740-753

Structure:

Androgen receptor. Chain: a. Synonym: dihydrotestosterone receptor. Engineered: yes. Mutation: yes. Nuclear receptor coactivator 2. Chain: b. Synonym: ncoa-2, transcriptional intermediary factor 2. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ar, dhtr, nr3c4. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: ncoa2, tif2. Expression_system_taxid: 562

Resolution:

1.92Å R-factor: 0.184 R-free: 0.221

Authors:

R.T.Gampe

Key ref:

E.B.Askew et al. (2007). Modulation of androgen receptor activation function 2 by testosterone and dihydrotestosterone. J Biol Chem, 282, 25801-25816. PubMed id: 17591767 DOI: 10.1074/jbc.M703268200

Date:

07-Jun-07 Release date: 24-Jul-07

Protein chain

P10275  (ANDR_HUMAN) -  Androgen receptor from Homo sapiens

Seq: 920 a.a.

Struc: 247 a.a.*

Protein chain

Q15596  (NCOA2_HUMAN) -  Nuclear receptor coactivator 2 from Homo sapiens

Seq: 1464 a.a.

Struc: 13 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: Chains A, B: E.C.?

DOI no: 10.1074/jbc.M703268200

J Biol Chem 282:25801-25816 (2007)

PubMed id: 17591767

Modulation of androgen receptor activation function 2 by testosterone and dihydrotestosterone.

E.B.Askew, R.T.Gampe, T.B.Stanley, J.L.Faggart, E.M.Wilson.

ABSTRACT

The androgen receptor (AR) is transcriptionally activated by high affinity binding of testosterone (T) or its 5alpha-reduced metabolite, dihydrotestosterone (DHT), a more potent androgen required for male reproductive tract development. The molecular basis for the weaker activity of T was investigated by determining T-bound ligand binding domain crystal structures of wild-type AR and a prostate cancer somatic mutant complexed with the AR FXXLF or coactivator LXXLL peptide. Nearly identical interactions of T and DHT in the AR ligand binding pocket correlate with similar rates of dissociation from an AR fragment containing the ligand binding domain. However, T induces weaker AR FXXLF and coactivator LXXLL motif interactions at activation function 2 (AF2). Less effective FXXLF motif binding to AF2 accounts for faster T dissociation from full-length AR. T can nevertheless acquire DHT-like activity through an AR helix-10 H874Y prostate cancer mutation. The Tyr-874 mutant side chain mediates a new hydrogen bonding scheme from exterior helix-10 to backbone protein core helix-4 residue Tyr-739 to rescue T-induced AR activity by improving AF2 binding of FXXLF and LXXLL motifs. Greater AR AF2 activity by improved core helix interactions is supported by the effects of melanoma antigen gene protein-11, an AR coregulator that binds the AR FXXLF motif and targets AF2 for activation. We conclude that T is a weaker androgen than DHT because of less favorable T-dependent AR FXXLF and coactivator LXXLL motif interactions at AF2.

Selected figure(s)

Figure 8.
FIGURE 8. Potential A-ring and water mediated H-bonding schemes for T and DHT. Predicted A-ring H-bond distances and angles are shown based on the tetrahedral geometry of conserved structural water HOH1 (see Footnote 3 and see Table 4). Arrowhead with black dashed lines indicate the direction of donated H-bonds and orange dashed lines designate potential interactions with neighboring polar atoms of WT AR LBD bound to T and AR-(20-30) FXXLF peptide (tan) (A); WT AR LBD bound to DHT and GRIP-1-(740-752) LXXLL peptide (green) (42) (B); and the superimposition of A and B (C). Superior hydrophilic properties and a shorter distance are thought to enhance the HOH1 to T 3-keto O H-bond over that in DHT.

Figure 11.
FIGURE 11. Structural differences between the steroid and nonsteroidal ligand binding pockets. Superimposition of WT AR LBD crystal structures bound with an FXXLF peptide and T (brown), DHT (green) (18), R1881 (magenta) (4), and S-1 bicalutamide agonist analog (cyan) (43) and AR-H874Y LBD bound to the AR FXXLF peptide and T (yellow). The C-19 bridgehead methyl group on T and DHT forces the Met-745 and Trp-741 side chains away from the steroid A-ring. For R1881 and S-1, the absence of an equivalent methyl group allows these side chains to adopt different rotamers that fill the vacated space above ring A^4. The para-fluoro phenyl group on S1 extends into the space between helix-12 Met-895 and helix-5 Met-742 and directs Trp-741 to a third unique conformation. Appropriate para-phenyl substituents are thought to stabilize the AR LBD core by interacting with HOH3 (43).

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2007, 282, 25801-25816) copyright 2007.

Figures were selected by an automated process.