Dataset Information

Allosteric Modulation of G Protein Coupled Receptors by Cytoplasmic, Transmembrane and Extracellular Ligands.

ABSTRACT: G protein coupled receptors (GPCRs) bind diverse classes of ligands, and depending on the receptor, these may bind in their transmembrane or the extracellular domains, demonstrating the principal ability of GPCRs to bind ligand in either domains. Most recently, it was also observed that small molecule ligands can bind in the cytoplasmic domain, and modulate binding and response to extracellular or transmembrane ligands. Thus, all three domains in GPCRs are potential sites for allosteric ligands, and whether a ligand is allosteric or orthosteric depends on the receptor. Here, we will review the evidence supporting the presence of putative binding pockets in all three domains of GPCRs and discuss possible pathways of communication between these pockets.

SUBMITTER: Yanamala N

PROVIDER: S-EPMC3760430 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Allosteric Modulation of G Protein Coupled Receptors by Cytoplasmic, Transmembrane and Extracellular Ligands.

Yanamala Naveena N Klein-Seetharaman Judith J

Pharmaceuticals (Basel, Switzerland) 20101001 10

G protein coupled receptors (GPCRs) bind diverse classes of ligands, and depending on the receptor, these may bind in their transmembrane or the extracellular domains, demonstrating the principal ability of GPCRs to bind ligand in either domains. Most recently, it was also observed that small molecule ligands can bind in the cytoplasmic domain, and modulate binding and response to extracellular or transmembrane ligands. Thus, all three domains in GPCRs are potential sites for allosteric ligands, ...[more]

PMID: 24009470

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Project description:The ligand-binding sites of many G protein-coupled receptors (GPCRs) are situated around and deeply embedded within the central pocket formed by their seven transmembrane-spanning α-helical domains. Generally, these binding sites are assumed accessible to endogenous ligands from the aqueous phase. Recent advances in the structural biology of GPCRs, along with biophysical and computational studies, suggest that amphiphilic and lipophilic molecules may gain access to these receptors by first partitioning into the membrane and then reaching the binding site via lateral diffusion through the lipid bilayer. In addition, several crystal structures of class A and class B GPCRs bound to their ligands offer unprecedented details on the existence of lipid-facing allosteric binding sites outside the transmembrane helices that can only be reached via lipid pathways. The highly organized structure of the lipid bilayer may direct lipophilic or amphiphilic drugs to a specific depth within the bilayer, changing local concentration of the drug near the binding site and affecting its binding kinetics. Additionally, the constraints of the lipid bilayer, including its composition and biophysical properties, may play a critical role in "pre-organizing" ligand molecules in an optimal orientation and conformation to facilitate receptor binding. Despite its clear involvement in molecular recognition processes, the critical role of the membrane in binding ligands to lipid-exposed transmembrane binding sites remains poorly understood and warrants comprehensive investigation. Understanding the mechanistic basis of the structure-membrane interaction relationship of drugs will not only provide useful insights about receptor binding kinetics but will also enhance our ability to take advantage of the apparent membrane contributions when designing drugs that target transmembrane proteins with improved efficacy and safety. In this minireview, we summarize recent structural and computational studies on membrane contributions to binding processes, elucidating both lipid pathways of ligand access and binding mechanisms for several orthosteric and allosteric ligands of class A and class B GPCRs.

Dataset Information

Allosteric Modulation of G Protein Coupled Receptors by Cytoplasmic, Transmembrane and Extracellular Ligands.

Publications

Allosteric Modulation of G Protein Coupled Receptors by Cytoplasmic, Transmembrane and Extracellular Ligands.

Similar Datasets

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