GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
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Journal | Science (New York, N.Y.) |
Volume | 318 |
Issue number | 5854 |
Pages (from-to) | 1266-73 |
Number of pages | 8 |
ISSN | 0036-8075 |
DOIs | |
Publication status | Published - 23 Nov 2007 |
- Adrenergic beta-Agonists, Adrenergic beta-Antagonists, Amino Acid Sequence, Bacteriophage T4, Binding Sites, Cell Line, Cell Membrane, Crystallization, Crystallography, X-Ray, Drug Inverse Agonism, Humans, Immunoglobulin Fab Fragments, Ligands, Models, Molecular, Molecular Sequence Data, Muramidase, Propanolamines, Protein Conformation, Protein Structure, Secondary, Protein Structure, Tertiary, Receptors, Adrenergic, beta-2, Recombinant Fusion Proteins
Research areas
ID: 120588742