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

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 Å 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.

Met909 Plays a Key Role in the Activation of the Progesterone Receptor and Also in the High Potency of 13-Ethyl Progestins

“…It is noteworthy that Asn719 is conserved in the other 3-oxosteroids receptors. The strong hydrogen bond between the Asn705 of the AR, and the 17␤-hydroxyl group of androgen ligands plays a crucial role in androgen binding and AR activation (Matias et al, 2000;Poujol et al, 2000;Pereira de Jésus-Tran et al, 2006). In a similar way, GR and MR activation are dependent on the contact between the 21-hydroxyl group of ligands, and the GRN564 and MRN770 (Fagart et al, 1998;Hellal-Levy et al, 1999;Lind et al, 2000;Bledsoe et al, 2002;Bledsoe et al, 2005).…”

The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide

“…2A). In this agonistic conformation, the interactions of testosterone (T) or DHT with the R753 side chain are crucial (31,32). However, if a similar interaction between R753 and enzalutamide is preserved, the latter cannot be accommodated in the agonistic conformation of AR WT or AR T878A.…”

Splice variants in the proteome: a promising and challenging field to targeted drug discovery

“…The reasons for this advance involve not only AR, but also the participation of the glucocorticoid receptor (GR), which is involved with many signaling pathways as well as other nuclear receptors [50]. With the structures of both AR and GR elucidated [51,52], alternative splicing could interfere with the resistance of prostate cancer [53,54], reinforcing the need for more studies correlating the protein structure of splice variants and treatment responsiveness.…”