Dataset Information

A pharmacological organization of G protein-coupled receptors.

ABSTRACT: Protein classification typically uses structural, sequence or functional similarity. Here we introduce an orthogonal method that organizes proteins by ligand similarity, focusing on the class A G-protein-coupled receptor (GPCR) protein family. Comparing a ligand-based dendrogram to a sequence-based one, we identified GPCRs that were distantly linked by sequence but were neighbors by ligand similarity. Experimental testing of the ligands predicted to link three of these new pairs confirmed the predicted association, with potencies ranging from low nanomolar to low micromolar. We also predicted hundreds of non-GPCRs closely related to GPCRs by ligand similarity and confirmed several cases experimentally. Ligand similarities among these targets may reflect the conservation of identical ligands among unrelated receptors, which signal in different time domains. Our method integrates these apparently disparate receptors into chemically coherent circuits and suggests which of these receptors may be targeted by individual ligands.

SUBMITTER: Lin H

PROVIDER: S-EPMC3560304 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A pharmacological organization of G protein-coupled receptors.

Lin Henry H Sassano Maria F MF Roth Bryan L BL Shoichet Brian K BK

Nature methods 20130106 2

Protein classification typically uses structural, sequence or functional similarity. Here we introduce an orthogonal method that organizes proteins by ligand similarity, focusing on the class A G-protein-coupled receptor (GPCR) protein family. Comparing a ligand-based dendrogram to a sequence-based one, we identified GPCRs that were distantly linked by sequence but were neighbors by ligand similarity. Experimental testing of the ligands predicted to link three of these new pairs confirmed the pr ...[more]

PMID: 23291723

Similar Datasets

Project description:The ligands of certain G-protein coupled receptors (GPCRs) are membrane soluble and reach their target from the lipid bilayer. Lipid composition and dynamics will therefore modulate the activity of these receptors, but specific roles of lipid components, including the ubiquitous cholesterol (Chol), are not clear. We have probed the organization and dynamics of such a lipid-bilayer-penetrating ligand, the endogenous ligand for the κ-opioid receptor (KOR) dynorphin A (1-17) (DynA), using molecular dynamics (MD) simulations of DynA in cholesterol-depleted and cholesterol-enriched model membranes. DynA is found to penetrate deep inside fluid dimyristoylphosphatidylcholine (DMPC) bilayers, and resides with its N-terminal helix at ∼6 Å away from the bilayer midplane, in a tilted orientation, at an ∼50° angle with respect to the membrane normal. In contrast, DynA inside DMPC/Chol membranes with 20% cholesterol (DMPC/Chol) is situated with its helical segment ∼5 A higher, i.e., closer to the lipid/water interface and in a relatively vertical orientation. The DMPC membrane shows greater thinning around the insertion and permits a stronger influx of water inside the hydrocarbon core than the DMPC/Chol membranes. Relating these results to data about key GPCR residues that have been implicated in interactions with membrane-inserting GPCR ligands, we conclude that the position of DynA in DMPC/Chol, but not in pure DMPC, correlates with generally proposed GPCR ligand entry pathways. Our predictions provide a possible mechanistic explanation as to why DynA binding to KOR, and the subsequent activation of the receptor, is facilitated in cholesterol-enriched environments. A quantitative description of DynA-induced membrane deformations is obtained with a continuum theory of membrane deformations (CTMD) that is based on hydrophobic matching. Comparison with the MD data reveals the significance of the lipid tail packing energy contribution in the DMPC/Chol mixtures in predicting equilibrium membrane shape around DynA. On this basis, specific corrections are introduced to this energy term within the CTMD framework, thereby extending the applicability of the CTMD framework to lipid raft mixtures and their interactions with GPCR proteins and their ligands.

Dataset Information

A pharmacological organization of G protein-coupled receptors.

Publications

A pharmacological organization of G protein-coupled receptors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets