High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor

Vadim Cherezov; Daniel M Rosenbaum; Michael A Hanson; Søren Gøgsig Faarup Rasmussen; Foon Sun Thian; Tong Sun Kobilka; Hee-Jung Choi; Peter Kuhn; William I Weis; Brian K Kobilka; Raymond C Stevens

doi:10.1126/science.1150577

High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor

Vadim Cherezov, Daniel M Rosenbaum, Michael A Hanson, Søren Gøgsig Faarup Rasmussen, Foon Sun Thian, Tong Sun Kobilka, Hee-Jung Choi, Peter Kuhn, William I Weis, Brian K Kobilka, Raymond C Stevens

Neuropharm and Genetics

2587 Citations (Scopus)

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.

Original language	English
Journal	Science (New York, N.Y.)
Volume	318
Issue number	5854
Pages (from-to)	1258-65
Number of pages	8
ISSN	0036-8075
DOIs	https://doi.org/10.1126/science.1150577
Publication status	Published - 23 Nov 2007

Keywords

Bacteriophage T4
Binding Sites
Cell Membrane
Cholesterol
Crystallization
Crystallography, X-Ray
Drug Inverse Agonism
Humans
Ligands
Models, Molecular
Muramidase
Propanolamines
Protein Conformation
Protein Folding
Protein Structure, Secondary
Receptors, Adrenergic, beta-2
Recombinant Fusion Proteins
Rhodopsin
Static Electricity

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title = "High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor",

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.",

keywords = "Bacteriophage T4, Binding Sites, Cell Membrane, Cholesterol, Crystallization, Crystallography, X-Ray, Drug Inverse Agonism, Humans, Ligands, Models, Molecular, Muramidase, Propanolamines, Protein Conformation, Protein Folding, Protein Structure, Secondary, Receptors, Adrenergic, beta-2, Recombinant Fusion Proteins, Rhodopsin, Static Electricity",

author = "Vadim Cherezov and Rosenbaum, {Daniel M} and Hanson, {Michael A} and Rasmussen, {S{\o}ren G{\o}gsig Faarup} and Thian, {Foon Sun} and Kobilka, {Tong Sun} and Hee-Jung Choi and Peter Kuhn and Weis, {William I} and Kobilka, {Brian K} and Stevens, {Raymond C}",

year = "2007",

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T1 - High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor

AU - Cherezov, Vadim

AU - Rosenbaum, Daniel M

AU - Hanson, Michael A

AU - Rasmussen, Søren Gøgsig Faarup

AU - Thian, Foon Sun

AU - Kobilka, Tong Sun

AU - Choi, Hee-Jung

AU - Kuhn, Peter

AU - Weis, William I

AU - Kobilka, Brian K

AU - Stevens, Raymond C

PY - 2007/11/23

Y1 - 2007/11/23

N2 - 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.

AB - 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.

KW - Bacteriophage T4

KW - Binding Sites

KW - Cell Membrane

KW - Cholesterol

KW - Crystallization

KW - Crystallography, X-Ray

KW - Drug Inverse Agonism

KW - Humans

KW - Ligands

KW - Models, Molecular

KW - Muramidase

KW - Propanolamines

KW - Protein Conformation

KW - Protein Folding

KW - Protein Structure, Secondary

KW - Receptors, Adrenergic, beta-2

KW - Recombinant Fusion Proteins

KW - Rhodopsin

KW - Static Electricity

U2 - 10.1126/science.1150577

DO - 10.1126/science.1150577

M3 - Journal article

C2 - 17962520

SN - 0036-8075

VL - 318

SP - 1258

EP - 1265

JO - Science

JF - Science

IS - 5854

ER -

High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor

Abstract

Keywords

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