Predicting GPCR Promiscuity Using Binding Site Features

G protein-coupled receptors (GPCRs) represent a large family of signaling proteins that includes many therapeutic targets. GPCR ligands include odorants, tastants, and neurotransmitters and vary in size and properties. Dramatic chemical diversity may occur even among ligands of the same receptor. Our goal is to unravel the structural and chemical features that determine GPCRs’ promiscuity toward their ligands. We perform statistical analysis using more than 30 descriptors related to the sequence, physicochemical, structural, and energetic properties of the GPCR binding siteswe find that the chemical variability of antagonists significantly correlates with the binding site hydrophobicity and anticorrelates with the number of hydrogen bond donors in the binding site. The number of disulfide bridges in the extracellular region of a receptor anticorrelates with the range of molecular weights of its antagonists, highlighting the role of the entrance pathway in determining the size selectivity for GPCR antagonists. The predictive capability of the model is successfully validated using a separate set of GPCRs, using either X-ray structures or homology models

DataSheet2_Independent Evolution of Strychnine Recognition by Bitter Taste Receptor Subtypes.zip

<p>The 25 human bitter taste receptors (hT2Rs) recognize thousands of structurally and chemically diverse bitter substances. The binding modes of human bitter taste receptors hT2R10 and hT2R46, which are responsible for strychnine recognition, were previously established using site-directed mutagenesis, functional assays, and molecular modeling. Here we construct a phylogenetic tree and reconstruct ancestral sequences of the T2R10 and T2R46 clades. We next analyze the binding sites in view of experimental data to predict their ability to recognize strychnine. This analysis suggests that the common ancestor of hT2R10 and hT2R46 is unlikely to bind strychnine in the same mode as either of its two descendants. Estimation of relative divergence times shows that hT2R10 evolved earlier than hT2R46. Strychnine recognition was likely acquired first by the earliest common ancestor of the T2R10 clade before the separation of primates from other mammals, and was highly conserved within the clade. It was probably independently acquired by the common ancestor of T2R43-47 before the homo-ape speciation, lost in most T2Rs within this clade, but enhanced in the hT2R46 after humans diverged from the rest of primates. Our findings suggest hypothetical strychnine T2R receptors in several species, and serve as an experimental guide for further study. Improved understanding of how bitter taste receptors acquire the ability to be activated by particular ligands is valuable for the development of sensors for bitterness and for potential toxicity.</p

DataSheet1_Independent Evolution of Strychnine Recognition by Bitter Taste Receptor Subtypes.pdf

<p>The 25 human bitter taste receptors (hT2Rs) recognize thousands of structurally and chemically diverse bitter substances. The binding modes of human bitter taste receptors hT2R10 and hT2R46, which are responsible for strychnine recognition, were previously established using site-directed mutagenesis, functional assays, and molecular modeling. Here we construct a phylogenetic tree and reconstruct ancestral sequences of the T2R10 and T2R46 clades. We next analyze the binding sites in view of experimental data to predict their ability to recognize strychnine. This analysis suggests that the common ancestor of hT2R10 and hT2R46 is unlikely to bind strychnine in the same mode as either of its two descendants. Estimation of relative divergence times shows that hT2R10 evolved earlier than hT2R46. Strychnine recognition was likely acquired first by the earliest common ancestor of the T2R10 clade before the separation of primates from other mammals, and was highly conserved within the clade. It was probably independently acquired by the common ancestor of T2R43-47 before the homo-ape speciation, lost in most T2Rs within this clade, but enhanced in the hT2R46 after humans diverged from the rest of primates. Our findings suggest hypothetical strychnine T2R receptors in several species, and serve as an experimental guide for further study. Improved understanding of how bitter taste receptors acquire the ability to be activated by particular ligands is valuable for the development of sensors for bitterness and for potential toxicity.</p

Ribbon representation of the six αβα-core connectivity-based structural classes

<p><b>Copyright information:</b></p><p>Taken from "Topology of Type II REases revisited; structural classes and the common conserved core"</p><p></p><p>Nucleic Acids Research 2007;35(7):2227-2237.</p><p>Published online 16 Mar 2007</p><p>PMCID:PMC1874628.</p><p>© 2007 The Author(s)</p> The α-helices H1 and H2, and β-strands S1 to S5, constituting the αβα-core, are shown for superposed structures belonging to each one of the new structural classes: () Structures 1cfr, 1knvA, 1na6B, 1wtdB, 1dc1A, 2fokA, 1fiuA and 1qc9A for class I in stereo view; () 1sdoA, 2bamA and 1dfmA for class II; 1sa3A and 1ynmA for class III; () 1xhvA, 1b94A, 1iawA and 1dmuA for class IV in stereo view; () 3pviA for class V and 2ixs for class VI

Aldehyde Recognition and Discrimination by Mammalian Odorant Receptors via Functional Group-Specific Hydration Chemistry

The mammalian odorant receptors (ORs) form a chemical-detecting interface between the atmosphere and the nervous system. This large gene family is composed of hundreds of membrane proteins predicted to form as many unique small molecule binding niches within their G-protein coupled receptor (GPCR) framework, but very little is known about the molecular recognition strategies they use to bind and discriminate between small molecule odorants. Using rationally designed synthetic analogs of a typical aliphatic aldehyde, we report evidence that among the ORs showing specificity for the aldehyde functional group, a significant percentage detect the aldehyde through its ability to react with water to form a 1,1-<i>geminal</i> (<i>gem</i>)-diol. Evidence is presented indicating that the rat OR-I7, an often-studied and modeled OR known to require the aldehyde function of octanal for activation, is likely one of the <i>gem</i>-diol activated receptors. A homology model based on an activated GPCR X-ray structure provides a structural hypothesis for activation of OR-I7 by the <i>gem</i>-diol of octanal