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Analysis of tractable allosteric sites in G protein-coupled receptors.

ABSTRACT: Allosteric modulation of G protein-coupled receptors represent a promising mechanism of pharmacological intervention. Dramatic developments witnessed in the structural biology of membrane proteins continue to reveal that the binding sites of allosteric modulators are widely distributed, including along protein surfaces. Here we restrict consideration to intrahelical and intracellular sites together with allosteric conformational locks, and show that the protein mapping tools FTMap and FTSite identify 83% and 88% of such experimentally confirmed allosteric sites within the three strongest sites found. The methods were also able to find partially hidden allosteric sites that were not fully formed in X-ray structures crystallized in the absence of allosteric ligands. These results confirm that the intrahelical sites capable of binding druglike allosteric modulators are among the strongest ligand recognition sites in a large fraction of GPCRs and suggest that both FTMap and FTSite are useful tools for identifying allosteric sites and to aid in the design of such compounds in a range of GPCR targets.

SUBMITTER: Wakefield AE

PROVIDER: S-EPMC6467999 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Analysis of tractable allosteric sites in G protein-coupled receptors.

Wakefield Amanda E AE Mason Jonathan S JS Vajda Sandor S Keserű György M GM

Scientific reports 20190416 1

Allosteric modulation of G protein-coupled receptors represent a promising mechanism of pharmacological intervention. Dramatic developments witnessed in the structural biology of membrane proteins continue to reveal that the binding sites of allosteric modulators are widely distributed, including along protein surfaces. Here we restrict consideration to intrahelical and intracellular sites together with allosteric conformational locks, and show that the protein mapping tools FTMap and FTSite ide ...[more]

PMID: 30992500

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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 ?-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

Analysis of tractable allosteric sites in G protein-coupled receptors.

Publications

Analysis of tractable allosteric sites in G protein-coupled receptors.

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