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Article

Overview of Nomenclature of Nuclear Receptors

Department of Cell Biology and Signal Transduction, Institut de Genetique et de Biologie Moleculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale U596, Illkirch, France (P.G.); Institut Pasteur de Lille, Institut National de la Santé et de la Recherche Médicale U545, Université de Lille II, Lille, France (B.S.); Experimental Sciences Institute of Research Servier, Suresnes, France (C.D., M.S.); and Laboratoire de Biologie Moleculaire de la Cellule, BioSciences Lyon-Gerland, École Normale Supérieure de Lyon, Lyon, France (V.L.)

Abstract

Introduction

Nomenclature

Nomenclature: Terms and Symbols

Structure/Function Analysis

The A/B Region

The DNA-Binding Domain

The D Region

The Ligand-Binding Domain

Structure of the Ligand-Binding Domain

Dimer Interface

The Ligand-Binding Pocket

The AF-2 Function

Transcriptional Regulation by the Nuclear Receptors

DNA Recognition

Transcriptional Activation

Transcriptional Repression

Molecular Basis of Corepressor/Coactivator Exchange

Kinetics and Nuclear Receptor Turnover

Transrepression

Post-Translational Modifications

Nongenomic Effects

Nuclear Receptors and Ligands

True Orphans

Ligand-Regulated Nuclear Receptors

Ligand Specificity

Different Classes of Ligands

Nuclear Receptor Antagonists

Inverse Agonists

Partial Agonists

Selective Nuclear Receptor Modulators

Nuclear receptor pharmacology has, to a certain extent, led the way, compared with other receptor systems, in the appreciation that ligands may exert very diverse pharmacology, based on their individual chemical structure and the allosteric changes induced in the receptor/accessory protein complex. This can lead to very selective pharmacological effects, which may not necessarily be predicted from the experience with other agonists/partial agonists/antagonists. If this is the case, then drug discovery may be back to drug-specific pharmacology (where each drug may have an original profile), rather than specific-drug pharmacology (where agents specific for a receptor have a distinct profile). As functional selectivity is indeed a crucial mechanism to be considered when going through the drug discovery development process, then initial screens using reconstituted systems may not show the appropriate pharmacology, simply because the required stoichiometry of corepressors and coactivators may not be present to select the best compounds; therefore, multiple effector systems are necessary to screen for differential activation, and, even then, screening with in vivo pathophysiological models may ultimately be required for the selection process—a massive but necessary task for pharmacologists. Thus, the characterization of nuclear receptors and their associated proteins and the ligands that interact with them will remain a challenge to pharmacologists.

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