ABSTRACT
Drugs frequently require interactions with multiple targets-via a process known as polypharmacology-to achieve their therapeutic actions. Currently, drugs targeting several serotonin receptors, including the 5-HT2C receptor, are useful for treating obesity, drug abuse, and schizophrenia. The competing challenges of developing selective 5-HT2C receptor ligands or creating drugs with a defined polypharmacological profile, especially aimed at G protein-coupled receptors (GPCRs), remain extremely difficult. Here, we solved two structures of the 5-HT2C receptor in complex with the highly promiscuous agonist ergotamine and the 5-HT2A-C receptor-selective inverse agonist ritanserin at resolutions of 3.0 Å and 2.7 Å, respectively. We analyzed their respective binding poses to provide mechanistic insights into their receptor recognition and opposing pharmacological actions. This study investigates the structural basis of polypharmacology at canonical GPCRs and illustrates how understanding characteristic patterns of ligand-receptor interaction and activation may ultimately facilitate drug design at multiple GPCRs.
Subject(s)
Ergotamine/chemistry , Receptor, Serotonin, 5-HT2C/chemistry , Ritanserin/chemistry , Serotonin 5-HT2 Receptor Agonists/chemistry , Serotonin 5-HT2 Receptor Antagonists/chemistry , HEK293 Cells , Humans , Obesity/drug therapy , Obesity/metabolism , Protein Domains , Receptor, Serotonin, 5-HT2C/metabolism , Schizophrenia/drug therapy , Schizophrenia/metabolism , Structure-Activity Relationship , Substance-Related Disorders/drug therapy , Substance-Related Disorders/metabolismABSTRACT
G-protein-coupled receptors (GPCRs) transduce physiological and sensory stimuli into appropriate cellular responses and mediate the actions of one-third of drugs. GPCR structural studies have revealed the general bases of receptor activation, signaling, drug action and allosteric modulation, but so far cover only 13% of nonolfactory receptors. We broadly surveyed the receptor modifications/engineering and methods used to produce all available GPCR crystal and cryo-electron microscopy (cryo-EM) structures, and present an interactive resource integrated in GPCRdb ( http://www.gpcrdb.org ) to assist users in designing constructs and browsing appropriate experimental conditions for structure studies.
Subject(s)
Computational Biology/methods , Internet , Receptors, G-Protein-Coupled/genetics , Allosteric Site , Animals , Cattle , Cryoelectron Microscopy , Crystallography, X-Ray , Databases, Protein , Drug Design , Glycosylation , HEK293 Cells , Humans , Mutation , Phosphorylation , Protein Domains , Protein Engineering , Rhodopsin/chemistry , Signal Transduction , SoftwareABSTRACT
Class 1 cytokine receptors regulate essential biological processes through complex intracellular signalling networks. However, the structural platform for understanding their functions is currently incomplete as structure-function studies of the intracellular domains (ICDs) are critically lacking. The present study provides the first comprehensive structural characterization of any cytokine receptor ICD and demonstrates that the human prolactin (PRL) receptor (PRLR) and growth hormone receptor (GHR) ICDs are intrinsically disordered throughout their entire lengths. We show that they interact specifically with hallmark lipids of the inner plasma membrane leaflet through conserved motifs resembling immuno receptor tyrosine-based activation motifs (ITAMs). However, contrary to the observations made for ITAMs, lipid association of the PRLR and GHR ICDs was shown to be unaccompanied by changes in transient secondary structure and independent of tyrosine phosphorylation. The results of the present study provide a new structural platform for studying class 1 cytokine receptors and may implicate the membrane as an active component regulating intracellular signalling.