The 2.0 Å crystal structure of the ERα ligand‐binding domain complexed with lasofoxifene

Abstract

Lasofoxifene is a new and potent selective estrogen receptor modulator (SERM). The structural basis of its interaction with the estrogen receptor has been investigated by crystallographic analysis of its complex with the ligand-binding domain of estrogen receptor a at a resolution of 2.0 Å . As with other SERMs, lasofoxifene diverts the receptor from its agonist-bound conformation by displacing the C-terminal AF-2 helix into the site at which the LXXLL motif of coactivator proteins would otherwise be able to bind. Lasofoxifene achieves this effect by occupying the space normally filled by residue Leu 540, as well as by modulating the conformation of residues of helix 11 (His 524, Leu 525). A welldefined salt bridge between lasofoxifene and Asp 351 suggests that charge neutralization in this region of the receptor may explain the some of the antiestrogenic effects of lasofoxifene. The results suggest general features of ERa/SERM recognition, and add a new dimension to efforts to rationalize differences between the biological activity profiles exhibited by these important pharmacological agents.

Nuclear Receptors and Their Selective Pharmacologic Modulators

“…Clinical data support the use of lasofoxifene in the prevention and treatment of osteoporosis and treatment of vaginal atrophy in postmenopausal women without an increased risk of endometrial cancer but with an increased risk of venous thromboembolic events (Bachmann et al, 2005;McClung et al, 2006b;Taylor, 2009;Cummings et al, 2010;Gennari et al, 2010). From a structural perspective, much like tamoxifen and raloxifene, lasofoxifene displaces helix 12 in the LBD from the agonist position to block the AF-2 coregulator-binding surface (Vajdos et al, 2007).…”

Drug Design Approaches to Manipulate the Agonist-Antagonist Equilibrium in Steroid Receptors

“…Numerous reviews of these two studies have been published Kong, Pike, and Hubbard, 2003;MuellerFahrnow and Egner, 1999; as have many further studies on the X-ray structures of SERMs, full antagonists and full agonists bound to the ERs Dykstra et al, 2007;Heldring et al, 2007;Kim et al, 2004;Renaud et al, 2003;Renaud et al, 2005;Tan et al, 2005;Vajdos et al, 2007). The same helix-12 clash has also been demonstrated for AR (Cantin et al, 2007) and GR (Schoch et al, 2010) in recent X-ray structure determination studies.…”

Three-Dimensional Quantitative Structure-Activity Relationships of flavonoids and estrogen receptors based on docking

“…The crystal structure of the estrogen receptor and lasofoxifene complex was obtained from Protein Data bank (PDB ID: 2OUZ) [21], and the lasofoxifene and estrogen receptor was isolated from the complex. Water molecules were removed and polar hydrogen was added by using SYBYL 7.3 programming package.…”