Constitutive activity and ligand-dependent activation of the nuclear receptor CAR—insights from molecular dynamics simulations

✍ Scribed by Björn Windshügel; Antti Poso

• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: English
• Weight: 434 KB
• Volume: 24
• Category: Article
• ISSN: 0952-3499
• DOI: 10.1002/jmr.1132

✦ Synopsis

Abstract

The constitutive androstane receptor (CAR) possesses, unlike most other nuclear receptors, a pronounced basal activity in vitro whose structural basis is still not fully understood. Using comparative molecular dynamics simulations of CAR X‐ray crystal structures, we evaluated the molecular basis for constitutive activity and ligand‐dependent receptor activation. Our results suggest that a combination of van der Waals interactions and hydrogen bonds is required to maintain the activation helix in the active conformation also in absence of a ligand. Furthermore, we identified conformational rearrangements within the ligand‐binding pocket upon agonist binding and an influence of CAR inducers pregnanedione and CITCO on the helical conformation of the activation helix. Based on the results a model for ligand‐dependent CAR activation is suggested. Copyright © 2011 John Wiley & Sons, Ltd.