PDBsum entry 2amb

Hormone/growth factor receptor

PDB id: 2amb

Contents

Protein chain

246 a.a. *

Ligands

SO4

17H

DTT

EPE

GOL

Waters ×192

* Residue conservation analysis

PDB id:

2amb

Name:

Hormone/growth factor receptor

Title:

Crystal structure of human androgen receptor ligand binding domain in complex with tetrahydrogestrinone

Structure:

Androgen receptor. Chain: a. Fragment: ligand binding domain. Synonym: dihydrotestosterone receptor. Engineered: yes

Source:

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

Resolution:

1.75Å R-factor: 0.186 R-free: 0.209

Authors:

K.Pereira De Jesus-Tran,P.-L.Cote,L.Cantin,J.Blanchet,F.Labrie, R.Breton

Key ref:

K.Pereira de Jésus-Tran et al. (2006). Comparison of crystal structures of human androgen receptor ligand-binding domain complexed with various agonists reveals molecular determinants responsible for binding affinity. Protein Sci, 15, 987-999. PubMed id: 16641486 DOI: 10.1110/ps.051905906

Date:

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

Protein chain

P10275  (ANDR_HUMAN) -  Androgen receptor from Homo sapiens

Seq: 920 a.a.

Struc: 246 a.a.

DOI no: 10.1110/ps.051905906

Protein Sci 15:987-999 (2006)

PubMed id: 16641486

Comparison of crystal structures of human androgen receptor ligand-binding domain complexed with various agonists reveals molecular determinants responsible for binding affinity.

K.Pereira de Jésus-Tran, P.L.Côté, L.Cantin, J.Blanchet, F.Labrie, R.Breton.

ABSTRACT

Androgens exert their effects by binding to the highly specific androgen receptor (AR). In addition to natural potent androgens, AR binds a variety of synthetic agonist or antagonist molecules with different affinities. To identify molecular determinants responsible for this selectivity, we have determined the crystal structure of the human androgen receptor ligand-binding domain (hARLBD) in complex with two natural androgens, testosterone (Testo) and dihydrotestosterone (DHT), and with an androgenic steroid used in sport doping, tetrahydrogestrinone (THG), at 1.64, 1.90, and 1.75 A resolution, respectively. Comparison of these structures first highlights the flexibility of several residues buried in the ligand-binding pocket that can accommodate a variety of ligand structures. As expected, the ligand structure itself (dimension, presence, and position of unsaturated bonds that influence the geometry of the steroidal nucleus or the electronic properties of the neighboring atoms, etc.) determines the number of interactions it can make with the hARLBD. Indeed, THG--which possesses the highest affinity--establishes more van der Waals contacts with the receptor than the other steroids, whereas the geometry of the atoms forming electrostatic interactions at both extremities of the steroid nucleus seems mainly responsible for the higher affinity measured experimentally for DHT over Testo. Moreover, estimation of the ligand-receptor interaction energy through modeling confirms that even minor modifications in ligand structure have a great impact on the strength of these interactions. Our crystallographic data combined with those obtained by modeling will be helpful in the design of novel molecules with stronger affinity for the AR.

Selected figure(s)

Figure 1.
Molecular structures of the ligands used. DHT, dihydrotestosterone; Testo, testosterone; THG, tetrahydrogestrinone; R1881, methyltrienolone. Carbon and oxygen atoms of the steroids are numbered according to the standard steroid nomenclature and the cycles designated by letters. For THG, extra carbon atoms are numbered 20 and 21 for the 17[alpha]-ethyl group and 22 for the C18-methyl group.

Figure 5.
Double or unique Gln711 conformation in (A) Testo --, (B) DHT --, and (C) THG --hARLBD complexes. Electron density maps are contoured at 1[sigma].

The above figures are reprinted from an Open Access publication published by the Protein Society: Protein Sci (2006, 15, 987-999) copyright 2006.

Figures were selected by an automated process.