Analysis of crystal structures of LXRbeta in relation to plasticity of the ligand-binding domain upon ligand binding

• Published in: Chemical biology & drug design Vol. 71; no. 2; pp. 140 - 154
• Main Authors: Malini, Nagulapalli, Rajesh, Hariharan, Berwal, Pooja, Phukan, Samiron, Balaji, Vittukudi Narayanaiyengar
• Format: Journal Article
• Language: English
• Published: England 01-02-2008
• Subjects: Binding Sites; Crystallography, X-Ray; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - metabolism; Drug Design; Humans; Ligands; Liver X Receptors; Motion; Orphan Nuclear Receptors; Pliability; Protein Binding; Protein Conformation; Receptors, Cytoplasmic and Nuclear - chemistry; Receptors, Cytoplasmic and Nuclear - metabolism; Substrate Specificity
• ISSN: 1747-0285
• DOI: 10.1111/j.1747-0285.2007.00620.x

Liver X receptors (LXRs) are a member of the nuclear hormone receptor superfamily of ligand activated transcription factors. LXRs have gained importance as therapeutic targets because of their involvement in many diseases. Analysis of the protein-ligand complexes of X-ray crystallography-derived structures revealed that residues His435 and Trp457 act as a switch that mediates ligand activation. These residues show conservation for main chain (phi, psi) in His435 and moderate movement for Trp457. His435 in Helix11 (H11) is conserved in relation to Trp457 in Helix12 (H12). This shows that some induced fit effect can be incorporated while designing ligands for activation of LXR with relation to Trp457 rather than that of His435. Similarly, main chain movement in Phe329 and Leu330 showed significant conformational mobility leading to flexibility in the ligand-binding domain (LBD) along with Arg319 which has a moderate movement in (phi and psi) angles. It is interesting to know that for some sequence-ligand complex crystallizations using different conditions show considerable main chain and side chain mobility indicating plasticity in LBD of LXRbeta. This study supports our understanding the relative movement of residues in the LBD of LXRs upon ligand binding which can provide insight for designing of LXRs modulators.