GPCR Engineering Yields High-Resolution Structural Insights into ?2-Adrenergic Receptor Function

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192

作者：

DM Rosenbaum，V Cherezov，MA Hanson，SGF Rasmussen，FS Thian，TS Kobilka，HJ Choi，XJ Yao，WI Weis，RC Stevens

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摘要：

The β 2 -adrenergic receptor (β 2 AR) is a well-studied prototype for heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors (GPCRs) that respond to diffusible hormones and neurotransmitters. To overcome the structural flexibility of the β 2 AR and to facilitate its crystallization, we engineered a β 2 AR fusion protein in which T4 lysozyme (T4L) replaces most of the third intracellular loop of the GPCR ("β 2 AR-T4L") and showed that this protein retains near-native pharmacologic properties. Analysis of adrenergic receptor ligand-binding mutants within the context of the reported high-resolution structure of β 2 AR-T4L provides insights into inverse-agonist binding and the structural changes required to accommodate catecholamine agonists. Amino acids known to regulate receptor function are linked through packing interactions and a network of hydrogen bonds, suggesting a conformational pathway from the ligand-binding pocket to regions that interact with G proteins.

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关键词：

Humans Cell Line Cell Membrane Propanolamines Muramidase Adrenergic beta-Agonists Adrenergic beta-Antagonists Recombinant Fusion Proteins Receptors, Adrenergic, beta-2 Ligands