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

2007/10/25 by Daniel M. Rosenbaum, Vadim Cherezov, Michael A. Hanson +8 · 7 citations
Biochemistry, Genetics and Molecular Biology · Neuroscience · Agricultural and Biological Sciences · #Receptor Mechanisms and Signaling #Neuropeptides and Animal Physiology #Pharmacological Effects and Assays

paper · doi:10.1126/science.1150609

openalex publication_date 2007/10/25 · openalex created_date 2016/06/24 · openalex updated_date 2026/08/01

Abstract

The beta2-adrenergic receptor (beta2AR) 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 beta2AR and to facilitate its crystallization, we engineered a beta2AR fusion protein in which T4 lysozyme (T4L) replaces most of the third intracellular loop of the GPCR ("beta2AR-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 beta2AR-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.

Citations

• High-Resolution Crystal Structure of an Engineered Human β 2 -Adrenergic G Protein–Coupled Receptor
• Signals from Chloroplasts Converge to Regulate Nuclear Gene Expression

Cited by

• Structure of an Agonist-Bound Human A 2A Adenosine Receptor
• The structure and function of G-protein-coupled receptors
• Crystal structure of the β2 adrenergic receptor–Gs protein complex
• Structure of a nanobody-stabilized active state of the β2 adrenoceptor
• Molecular signatures of G-protein-coupled receptors
• Structure and function of an irreversible agonist-β2 adrenoceptor complex
• G protein-coupled receptor [wikipedia]