High-resolution Crystal Structure of an Engineered Human Beta2-adrenergic G Protein-coupled Receptor

Overview

Journal Science

Specialty Science

Date 2007 Oct 27

PMID 17962520

Citations 1351

Authors

Vadim Cherezov

Daniel M Rosenbaum

Michael A Hanson

Soren G F Rasmussen

Foon Sun Thian

Tong Sun Kobilka

Hee-Jung Choi

Peter Kuhn

William I Weis

Brian K Kobilka

Raymond C Stevens

Affiliations

Soon will be listed here.

Abstract

Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors constitute the largest family of eukaryotic signal transduction proteins that communicate across the membrane. We report the crystal structure of a human beta2-adrenergic receptor-T4 lysozyme fusion protein bound to the partial inverse agonist carazolol at 2.4 angstrom resolution. The structure provides a high-resolution view of a human G protein-coupled receptor bound to a diffusible ligand. Ligand-binding site accessibility is enabled by the second extracellular loop, which is held out of the binding cavity by a pair of closely spaced disulfide bridges and a short helical segment within the loop. Cholesterol, a necessary component for crystallization, mediates an intriguing parallel association of receptor molecules in the crystal lattice. Although the location of carazolol in the beta2-adrenergic receptor is very similar to that of retinal in rhodopsin, structural differences in the ligand-binding site and other regions highlight the challenges in using rhodopsin as a template model for this large receptor family.

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