Field‐based comparison of ligand and coactivator binding sites of nuclear receptors

Abstract

A structure-based comparison of the ligand-binding domains of 35 nuclear receptors from five different subfamilies is presented. Their ligand and coactivator binding sites are characterized using knowledge-based contact preference fields for hydrophobic and hydrophilic interactions implemented in the MOE modeling environment. Additionally, for polar knowledge-based field points the preference for negative or positive electrostatic interactions is estimated using the Poisson-Boltzmann equation. These molecular-interaction fields are used to cluster the nuclear receptor family based on similarities of their binding sites. By analyzing the similarities and differences of hydrophobic and polar fields in binding pockets of related receptors it is possible to identify conserved interactions in ligand and coactivator binding pockets, which support e.g. design of specific ligands during lead optimization or virtual screening as docking filter. Examples of remarkable similarities between ligand binding sites of members from phylogenetically different nuclear receptor families (RXR, RAR, HNF4, NR5) and differences between closely related subtypes (LXR, RAR, TR) are discussed in more detail. Significant similarities and differences of coactivator binding sites are shown for NR3Cs, LXRs and PPARs.

Cinnamamides, Novel Liver X Receptor Antagonists that Inhibit Ligand-Induced Lipogenesis and Fatty Liver

“…6A, all compounds fitted comfortably into the binding pocket for the agonist T090, and the binding positions were similar. This finding was in line with the general belief that the ligand-binding domains of nuclear receptors accommodate mostly lipophilic ligands in predominantly hydrophobic pockets formed by residues of helices H5, H12, and other regions of the receptors (Wohlfahrt et al, 2009). We examined the docked pose of the most active antagonist (TFCA) in terms of hydrogen-bond interactions with the receptor and compared this structure to the X-ray pose of agonist T090 (Fig.…”

The retinoid X receptors and their ligands

“…Similarity cluster analyses of NR holo-LBP and CoA binding sites were conducted using the crystallographic structures of 177 human NRs from the PDB [62]. On the basis of the hydrophobic and polar contact preferences of 35 CoA-binding sites, RXRα and RXRβ of the RXRs (α, β, and γ, which were represented by respective PDB structures 1MV9, 1UHL, and 2GL8) were most closely related.…”

Visually Interpretable Models of Kinase Selectivity Related Features Derived from Field-Based Proteochemometrics

“…We have developed and automated several methods that create and compare polar and lipophilic knowledge-based fields 21 or include electrostatic information. 23 The desolvation of binding pockets is a main determinant of ligand affinity and difficult to estimate, for example, with molecular interaction fields. Schrodinger's WaterMap software, 24 which is based on molecular dynamics and statistical thermodynamics, predicts positions and energetics of water in ligand binding pockets.…”

“…In this article, we demonstrate the creation of proteochemometric models using field-based descriptions of the binding sites of kinases. We have developed and automated several methods that create and compare polar and lipophilic knowledge-based fields or include electrostatic information . The desolvation of binding pockets is a main determinant of ligand affinity and difficult to estimate, for example, with molecular interaction fields.…”