GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function. / Rosenbaum, Daniel M; Cherezov, Vadim; Hanson, Michael A; Rasmussen, Søren Gøgsig Faarup; Thian, Foon Sun; Kobilka, Tong Sun; Choi, Hee-Jung; Yao, Xiao-Jie; Weis, William I; Stevens, Raymond C; Kobilka, Brian K.

In: Science (New York, N.Y.), Vol. 318, No. 5854, 23.11.2007, p. 1266-73.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Rosenbaum, DM, Cherezov, V, Hanson, MA, Rasmussen, SGF, Thian, FS, Kobilka, TS, Choi, H-J, Yao, X-J, Weis, WI, Stevens, RC & Kobilka, BK 2007, 'GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function', Science (New York, N.Y.), vol. 318, no. 5854, pp. 1266-73. https://doi.org/10.1126/science.1150609

APA

Rosenbaum, D. M., Cherezov, V., Hanson, M. A., Rasmussen, S. G. F., Thian, F. S., Kobilka, T. S., Choi, H-J., Yao, X-J., Weis, W. I., Stevens, R. C., & Kobilka, B. K. (2007). GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function. Science (New York, N.Y.), 318(5854), 1266-73. https://doi.org/10.1126/science.1150609

Vancouver

Rosenbaum DM, Cherezov V, Hanson MA, Rasmussen SGF, Thian FS, Kobilka TS et al. GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function. Science (New York, N.Y.). 2007 Nov 23;318(5854):1266-73. https://doi.org/10.1126/science.1150609

Author

Rosenbaum, Daniel M ; Cherezov, Vadim ; Hanson, Michael A ; Rasmussen, Søren Gøgsig Faarup ; Thian, Foon Sun ; Kobilka, Tong Sun ; Choi, Hee-Jung ; Yao, Xiao-Jie ; Weis, William I ; Stevens, Raymond C ; Kobilka, Brian K. / GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function. In: Science (New York, N.Y.). 2007 ; Vol. 318, No. 5854. pp. 1266-73.

Bibtex

@article{158a19646ef54977a92bd6679c1a0d37,
title = "GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function",
abstract = "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.",
keywords = "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",
author = "Rosenbaum, {Daniel M} and Vadim Cherezov 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 Xiao-Jie Yao and Weis, {William I} and Stevens, {Raymond C} and Kobilka, {Brian K}",
year = "2007",
month = nov,
day = "23",
doi = "10.1126/science.1150609",
language = "English",
volume = "318",
pages = "1266--73",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "5854",

}

RIS

TY - JOUR

T1 - GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function

AU - Rosenbaum, Daniel M

AU - Cherezov, Vadim

AU - Hanson, Michael A

AU - Rasmussen, Søren Gøgsig Faarup

AU - Thian, Foon Sun

AU - Kobilka, Tong Sun

AU - Choi, Hee-Jung

AU - Yao, Xiao-Jie

AU - Weis, William I

AU - Stevens, Raymond C

AU - Kobilka, Brian K

PY - 2007/11/23

Y1 - 2007/11/23

N2 - 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.

AB - 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.

KW - Adrenergic beta-Agonists

KW - Adrenergic beta-Antagonists

KW - Amino Acid Sequence

KW - Bacteriophage T4

KW - Binding Sites

KW - Cell Line

KW - Cell Membrane

KW - Crystallization

KW - Crystallography, X-Ray

KW - Drug Inverse Agonism

KW - Humans

KW - Immunoglobulin Fab Fragments

KW - Ligands

KW - Models, Molecular

KW - Molecular Sequence Data

KW - Muramidase

KW - Propanolamines

KW - Protein Conformation

KW - Protein Structure, Secondary

KW - Protein Structure, Tertiary

KW - Receptors, Adrenergic, beta-2

KW - Recombinant Fusion Proteins

U2 - 10.1126/science.1150609

DO - 10.1126/science.1150609

M3 - Journal article

C2 - 17962519

VL - 318

SP - 1266

EP - 1273

JO - Science

JF - Science

SN - 0036-8075

IS - 5854

ER -

ID: 120588742