当前位置： SCI文献检索 > MOLECULAR PHARMACOLOGY期刊下所有文献 > Does the Lipid Bilayer Orchestrate Access and Binding of Ligands to Transmembrane Orthosteric/Allosteric Sites of G Protein-Coupled Receptors?

Does the Lipid Bilayer Orchestrate Access and Binding of Ligands to Transmembrane Orthosteric/Allosteric Sites of G Protein-Coupled Receptors?

Abstract：

: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.

journal_name

Mol Pharmacol

journal_title

Molecular pharmacology

authors

Szlenk CT,Gc JB,Natesan S

doi

10.1124/mol.118.115113

subject

Has Abstract

pub_date

2019-11-01 00:00:00

pages

527-541

issue

eissn

0026-895X

issn

1521-0111

pii

mol.118.115113

journal_volume

pub_type

杂志文章,评审

在线工具

Does the Lipid Bilayer Orchestrate Access and Binding of Ligands to Transmembrane Orthosteric/Allosteric Sites of G Protein-Coupled Receptors?