Language:

Structural Insights into the Dynamic Process of β2-Adrenergic Receptor Signaling

Cell, 2015-05, Vol.161 (5), p.1101-1111 [Peer Reviewed Journal]

2015 Elsevier Inc. ;Copyright © 2015 Elsevier Inc. All rights reserved. ;2015 Published by Elsevier Inc. 2015 ;ISSN: 0092-8674 ;EISSN: 1097-4172 ;DOI: 10.1016/j.cell.2015.04.043 ;PMID: 25981665

Full text available

Citations Cited by

Actions
1. Add to My Research
2. Remove from My Research
3. E-mail
4. Print
5. Permalink
6. Citation
7. EasyBib
8. EndNote
9. RefWorks
10. Delicious
11. Export RIS
12. Export BibTeX

Title:
Structural Insights into the Dynamic Process of β2-Adrenergic Receptor Signaling
Author: Manglik, Aashish ; Kim, Tae Hun ; Masureel, Matthieu ; Altenbach, Christian ; Yang, Zhongyu ; Hilger, Daniel ; Lerch, Michael T. ; Kobilka, Tong Sun ; Thian, Foon Sun ; Hubbell, Wayne L. ; Prosser, R. Scott ; Kobilka, Brian K.
Subjects: Adrenergic beta-Agonists - pharmacology ; Amino Acid Sequence ; Benzoxazines - pharmacology ; Humans ; Isoproterenol - metabolism ; Isoproterenol - pharmacology ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Molecular Sequence Data ; Nuclear Magnetic Resonance, Biomolecular ; Receptors, Adrenergic, beta-2 - chemistry ; Receptors, Adrenergic, beta-2 - metabolism ; Signal Transduction
Is Part Of: Cell, 2015-05, Vol.161 (5), p.1101-1111
Description: G-protein-coupled receptors (GPCRs) transduce signals from the extracellular environment to intracellular proteins. To gain structural insight into the regulation of receptor cytoplasmic conformations by extracellular ligands during signaling, we examine the structural dynamics of the cytoplasmic domain of the β2-adrenergic receptor (β2AR) using 19F-fluorine NMR and double electron-electron resonance spectroscopy. These studies show that unliganded and inverse-agonist-bound β2AR exists predominantly in two inactive conformations that exchange within hundreds of microseconds. Although agonists shift the equilibrium toward a conformation capable of engaging cytoplasmic G proteins, they do so incompletely, resulting in increased conformational heterogeneity and the coexistence of inactive, intermediate, and active states. Complete transition to the active conformation requires subsequent interaction with a G protein or an intracellular G protein mimetic. These studies demonstrate a loose allosteric coupling of the agonist-binding site and G-protein-coupling interface that may generally be responsible for the complex signaling behavior observed for many GPCRs. [Display omitted] •Two inactive states predominate in unliganded and antagonist-bound β2AR•Agonists increase structural heterogeneity in β2AR cytoplasmic domains•The agonist-binding pocket and cytoplasmic surface have weak allosteric coupling•Complete receptor activation requires G protein or a mimetic nanobody A combination of spectroscopic methods examining the dynamics and structure of the β2-adrenergic receptor reveals a loose allosteric coupling of the agonist-binding site and G-protein-coupling interface that shapes downstream signaling pathways.
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 0092-8674
EISSN: 1097-4172
DOI: 10.1016/j.cell.2015.04.043
PMID: 25981665
Source: Cell Press Free Archives
MEDLINE

Back to results list


INSPIRE LIBRARY - TON DUC THANG UNIVERSITY	(84-028) 37 755 057	Feedback
19 Nguyen Huu Tho St. Dist.7, HCM	thuvien@tdtu.edu.vn	Feedback

Structural Insights into the Dynamic Process of β2-Adrenergic Receptor Signaling

2015 Elsevier Inc. ;Copyright © 2015 Elsevier Inc. All rights reserved. ;2015 Published by Elsevier Inc. 2015 ;ISSN: 0092-8674 ;EISSN: 1097-4172 ;DOI: 10.1016/j.cell.2015.04.043 ;PMID: 25981665

Searching Remote Databases, Please Wait