Retinoid X receptors (RXR␣, -␤, and -␥) occupy a central position in the nuclear receptor superfamily, because they form heterodimers with many other family members and hence are involved in the control of a variety of (patho)physiologic processes. Selective RXR ligands, referred to as rexinoids, are already used or are being developed for cancer therapy and have promise for the treatment of metabolic diseases. However, important side effects remain associated with existing rexinoids. Here we describe the rational design and functional characterization of a spectrum of RXR modulators ranging from partial to pure antagonists and demonstrate their utility as tools to probe the implication of RXRs in cell biological phenomena. One of these ligands renders RXR activity particularly sensitive to coactivator levels and has the potential to act as a cell-specific RXR modulator. A combination of crystallographic and fluorescence anisotropy studies reveals the molecular details accounting for the agonist-to-antagonist transition and provides direct experimental evidence for a correlation between the pharmacological activity of a ligand and its impact on the structural dynamics of the activation helix H12. Using RXR and its cognate ligands as a model system, our correlative analysis of 3D structures and dynamic data provides an original view on ligand actions and enables the establishment of mechanistic concepts, which will aid in the development of selective nuclear receptor modulators.crystal structure ͉ ligand design ͉ nuclear receptor ͉ agonist ͉ antagonist N uclear Receptor (NR)-controlled gene expression relies on a mechanism in which NRs recruit coregulators that are part of multiprotein complexes. These complexes correspond to chromatin-modifying and transcription-initiating machineries that act at target gene promoters in a precisely timed and sequential fashion (1). The binding of a ligand to the ligandbinding domain (LBD) of NRs constitutes the initial step of this regulatory process. In this context, the C-terminal helix H12 of LBDs plays a key role, because its position, which depends on the bound ligand, determines the type of coregulator recruited by the receptor (2). Structural studies have shown that in agonistbound NR LBDs, H12 adopts the so-called ''active'' or ''holo'' conformation and provides a binding surface for short NR interaction motifs of coactivators (3). In contrast, antagonists prevent H12 from adopting the holo position (4).Therapeutically, retinoid X receptor (RXR)-selective ligands, referred to as rexinoids, are used in cancer therapy, and previously uncharacterized rexinoid-based therapeutic paradigms are currently being explored. In addition, rexinoids have promise for use in the therapy of metabolic diseases (5, 6), but important side effects associated with existing compounds limit their use. Improved understanding of the biological role and the structural biology of RXR (7, 8) will allow the synthesis of selective modulators that might overcome the limitations of current drugs. Here,...

A binding site for TSAO-m(3)T at the interface between the p66 and p51 subunits of HIV-1 reverse transcriptase (RT) and distinct from that of "classical" HIV-1 non-nucleoside inhibitors is proposed. The feasibility of the binding mode was assessed by carrying out nanosecond molecular dynamics simulations for the complexes of TSAO-m(3)T with reduced models of both the wild-type enzyme and a more sensitive R172A mutant. The molecular model is in agreement with a previous proposal, with known structure-activity and mutagenesis data for this unique class of inhibitors, and also with recent biochemical evidence indicating that TSAO analogues can affect enzyme dimerization. The relative importance of residues involved in dimer formation and TSAO-RT complex stabilization was assessed by a combination of surface area accessibility, molecular mechanics, and continuum electrostatics calculations. A structure-based modification introduced into the lead compound yielded a new derivative with improved antiviral activity.