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

  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},
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.

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 and

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 a

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.

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.

Investigation of allosteric coupling in human β2-adrenergic receptor in the presence of intracellular loop 3

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.

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.

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.

Betablockers at work: the crystal structure of the beta2-adrenergic receptor.

  • F. Hausch
  • Biology, Chemistry
    Angewandte Chemie
  • 2008
G-protein-coupled receptors (GPCR) are transmembrane proteins responsible for the transmission of extracellular signals into cells. With more than 800 members, they are the largest family of signal



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.

Structural basis of β‐adrenergic receptor function

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.

Agonist-induced conformational changes in the G-protein-coupling domain of the β2 adrenergic receptor

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.

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.

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.

Crystal structure of rhodopsin: a G-protein-coupled receptor.

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 structural

Structural Instability of a Constitutively Active G Protein-coupled Receptor

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.

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.

Advances in determination of a high-resolution three-dimensional structure of rhodopsin, a model of G-protein-coupled receptors (GPCRs).

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.