A Family-based Approach Reveals the Function of Residues in the Nuclear Receptor Ligand-binding Domain

Folkertsma, Simon; Noort, Paula van; Durme, Joost Van; Joosten, Han; Bettler, Emmanuel; Fleuren, Wilco W. M.; Oliveira, Laerte; Horn, Florence; Vlieg, Jacob de; Vriend, Gerrit

doi:10.1016/j.jmb.2004.05.075

Cited by 35 publications

(38 citation statements)

References 79 publications

(79 reference statements)

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“…about different activation mechanisms of NR subtypes. As the recruitment of cofactors is one of the most essential functions of the LBD, 12 comparison of coactivator sites should group NRs more according to similar function than to regulation, which is mostly determined by ligand binding. This type of structure-function relationship may be linked to NR distribution in different tissues as coactivator levels differ in these.…”

Section: Discussionmentioning

confidence: 99%

“…Structure-based approaches to functional analysis of the nuclear receptor family have been performed using structure-based alignments and comparison of ligand interactions in combination with literature data. [11][12][13] In this article we present another type of structure-based analysis of the nuclear receptor family, which is focused on essential molecular interaction fields within important functional regions like binding sites for regulating ligands or coactivators. Unlike residue-based comparisons, the effects from several parts of the binding sites are considered by this method in an additive and subtractive manner.…”

Section: Introductionmentioning

confidence: 99%

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

2009

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

2009

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“…[3,117,118] Overall, with increasing knowledge of NR functions, there is a high probability that novel, safer, and more effective medicines will be the eventual outcome. Important in this pursuit is the use of new technologies to profile ligands; this is the topic of the following and final section.…”

Section: Other Modulator Efforts: Pr Mr Ar Ppar Fxr and Lxrmentioning

confidence: 99%

The Nuclear Receptor Superfamily and Drug Discovery

2006

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“…X-ray structural confirmation has been obtained using shorter peptide versions of these cofactors, which retain key binding residues. Additionally, the amino acids lining this hydrophobic groove have been demonstrated to be the most conserved in NHRs, consistent with a central biological role for NHR cofactor binding [Folkertsma et al, 2004]. Novel methods like hydrogen/deuterium exchange mass spectroscopy have been able to locate the residues most affected by cofactor binding.…”

Section: Cofactor Bindingmentioning

confidence: 81%

Steroid nuclear hormone receptors: The allosteric conversation

Doweyko

2007

Drug Development Research

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Nuclear hormone receptors (NHRs) regulate gene expression by forming complexes with small molecule ligands, other proteins, and DNA. Specific ligands, which include steroids, thyroids, and retinoids, are responsible for the regulation of complex processes in cellular differentiation, homeostasis, reproduction, and development. NHRs responding to steroid ligands (e.g., androgens, estrogens, glucocorticoids, mineralocorticoids, and progesterones) are the focus of this review, in particular, highlighting the subtle relationships between ligand structure and receptor function. In the light of x-ray crystallographic information obtained in recent years, the structural organization of the ligand-and DNAbinding domains of steroid nuclear hormone receptors is well understood. Less clear is the means by which a steroid ligand affects the three-dimensional structure of a receptor, and how subtle differences in ligand structure can lead to major differences in functional activity (agonism, partial agonism, antagonism). Potential mechanisms by which ligands elicit such effects, statistical and mutational techniques used to identify key protein residues likely involved in the transmission of structural information, and novel sites of ligand-protein interaction are discussed in this review. Drug Dev Res 68: 95-106, 2007.

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A Family-based Approach Reveals the Function of Residues in the Nuclear Receptor Ligand-binding Domain

Cited by 35 publications

References 79 publications

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

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

The Nuclear Receptor Superfamily and Drug Discovery

Steroid nuclear hormone receptors: The allosteric conversation

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