Crystal structure of the human β2 adrenergic G-protein-coupled receptor

@article{Rasmussen2007CrystalSO,
title={Crystal structure of the human $\beta$2 adrenergic G-protein-coupled receptor},
author={S{\o}ren G. F. Rasmussen and Hee-Jung Choi and Daniel M. Rosenbaum and Tong Sun Kobilka and Foon Sun Thian and Patricia C. Edwards and Manfred Burghammer and Venkata R. P. Ratnala and Ruslan Sanishvili and Robert F. Fischetti and Gebhard F. X. Schertler and William I. Weis and Brian K. Kobilka},
journal={Nature},
year={2007},
volume={450},
pages={383-387}
}
Structural analysis of G-protein-coupled receptors (GPCRs) for hormones and neurotransmitters has been hindered by their low natural abundance, inherent structural flexibility, and instability in detergent solutions. [...] Key Result These differences may be responsible for the relatively high basal activity and structural instability of the β2AR, and contribute to the challenges in obtaining diffraction-quality crystals of non-rhodopsin GPCRs.Expand
1,554 Citations

Figures from this paper

Crystal Structures of the 2 -Adrenergic Receptor
G protein coupled receptors (GPCRs) constitute the largest family of membrane proteins in the human genome, and are responsible for the majority of signal transduction events involving hormones andExpand
Structure of a β1-adrenergic G-protein-coupled receptor
G-protein-coupled receptors have a major role in transmembrane signalling in most eukaryotes and many are important drug targets. Here we report the 2.7 Å resolution crystal structure of aExpand
High-Resolution Crystal Structure of an Engineered Human β2-Adrenergic G Protein–Coupled Receptor
Although the location of carazolol in the β2-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 rhodopin as a template model for this large receptor family. Expand
Crystal Structure of the β2Adrenergic Receptor-Gs protein complex
This crystal structure represents the first high-resolution view of transmembrane signalling by a GPCR and the most surprising observation is a major displacement of the α-helical domain of Gαs relative to the Ras-like GTPase domain. Expand
Investigation of allosteric coupling in human β2-adrenergic receptor in the presence of intracellular loop 3
• Chemistry, Medicine
• BMC Structural Biology
• 2016
Overall, the simulations indicated that starting with very inactive states, the receptor stayed almost irreversibly inhibited, which in turn decreased the overall mobility of the receptor. Expand
• Medicine, Biology
• Methods in enzymology
• 2013
This chapter summarizes the strategies and methods that have been successfully applied to the structural studies of βARs and discusses the spectacular insights into adrenergic receptor function that were obtained from the structures. Expand
GPCR Engineering Yields High-Resolution Structural Insights into β2-Adrenergic Receptor Function
Analysis of adrenergic receptor ligand-binding mutants within the context of the reported high-resolution structure of β2AR-T4L provides insights into inverse-agonist binding and the structural changes required to accommodate catecholamine agonists. Expand
Engineering G protein-coupled receptors to facilitate their structure determination.
• Biology, Medicine
• Current opinion in structural biology
• 2009
One of the opsin structures suggests how one of the highest conserved residues in GPCRs, Arg135(3.50) of the (E/D)RY motif in TM3, interacts directly with a bound peptide derived from the carboxy terminus of the alpha-subunit of the G protein (G(alpha)t). Expand
Structure-function of the G protein-coupled receptor superfamily.
• Biology, Medicine
• Annual review of pharmacology and toxicology
• 2013
High-resolution crystallography of G protein-coupled receptors shows the receptors as allosteric machines that are controlled not only by ligands but also by ions, lipids, cholesterol, and water, and helps redefine knowledge of how GPCRs recognize such a diverse array of ligands. Expand
Two distinct conformations of helix 6 observed in antagonist-bound structures of a β1-adrenergic receptor
Eight new structures of β1AR–M23 are compared, determined from crystallographically independent molecules in four different crystals with three different antagonists bound in the inactive R state and show clear electron density for cytoplasmic loop 3 linking transmembrane helices 5 and 6 that had not been seen previously. Expand

References

SHOWING 1-10 OF 56 REFERENCES
Coupling ligand structure to specific conformational switches in the β2-adrenoceptor
It is found that most partial agonists were as effective as full agonists in disrupting the ionic lock, and disruption of this important molecular switch is necessary, but not sufficient, for full activation of the β2-AR. Expand
Structural basis of β‐adrenergic receptor function
• Chemistry, Medicine
• FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 1989
Genetic analysis of the β‐adrenergic receptor revealed that the ligand binding domain of this receptor involves residues within the hydrophobic core of the protein, and structural similarities among G protein‐linked receptors suggest that this information should help define functionally important regions of other receptors of this class. Expand
Agonist-induced conformational changes in the G-protein-coupling domain of the β2 adrenergic receptor
• Chemistry, Medicine
• Proceedings of the National Academy of Sciences of the United States of America
• 2001
The authors' studies, when compared with studies of activation in rhodopsin, indicate a general mechanism for GPCR activation; however, a notable difference is the relatively slow kinetics of the conformational changes in the β2AR, which may reflect the different energetics of activation by diffusible ligands. Expand
Activation of the β2-Adrenergic Receptor Involves Disruption of an Ionic Lock between the Cytoplasmic Ends of Transmembrane Segments 3 and 6*
Evidence for the existence of an ionic lock that constrains the relative mobility of the cytoplasmic ends of TM3 and TM6 in the inactive state of the β2-adrenergic receptor is provided and ionic interactions between Asp/Glu3.49, Arg3.50, and Glu6.30 may constitute a common switch governing the activation of many rhodopsin-like G-protein-coupled receptors. Expand
Role of group-conserved residues in the helical core of β2-adrenergic receptor
To determine the role of group-conserved residues in the β2-adrenergic receptor (β2-AR), amino acid replacements guided by molecular modeling were carried out at key positions in transmembrane helices H2–H4 and allow insights into the roles of these residues in GPCR structure and function. Expand
Crystal structure of rhodopsin: a G-protein-coupled receptor.
• Biology, Medicine
• Chembiochem : a European journal of chemical biology
• 2002
Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) respond to a variety of different external stimuli and activate G proteins. GPCRs share many structuralExpand
Structural Instability of a Constitutively Active G Protein-coupled Receptor
• Chemistry, Medicine
• The Journal of Biological Chemistry
• 1997
It is proposed that the mutation that confers constitutive activity to the β2 adrenergic receptor removes some stabilizing conformational constraints, allowing CAM to more readily undergo transitions between the inactive and the active states and making the receptor more susceptible to denaturation. Expand
Probing the β2 Adrenoceptor Binding Site with Catechol Reveals Differences in Binding and Activation by Agonists and Partial Agonists*
Catechol is used as a molecular probe to identify mechanistic differences between β2AR activation by catecholamine agonists, such as isoproterenol, and by the structurally related non-catechol partial agonist salbutamol, showing unexpected differences in binding and activation by structurally similar agonists and partial agonists. Expand
A mutation-induced activated state of the beta 2-adrenergic receptor. Extending the ternary complex model.
• Medicine, Biology
• The Journal of biological chemistry
• 1993
The experimental findings with the mutant receptor cannot be adequately rationalized within the theoretical framework of the Ternary Complex Model, and an extended version of this model that includes an explicit isomerization of the receptor to an active state closely models all the findings for both the mutant and the wild-type receptors. Expand
Advances in determination of a high-resolution three-dimensional structure of rhodopsin, a model of G-protein-coupled receptors (GPCRs).
• Biology, Medicine
• Biochemistry
• 2001
The further refinement of rhodopsin is described and some clues about how the receptor could be activated by light are provided, to allow models, firmly based on the atomic-resolution structural information, to be further tested as to the conformational changes that these receptors undergo in going from the quiescent to the signaling state. Expand