Research Repository

Modeling GPCR active state conformations: The β<sub>2</sub>-adrenergic receptor

Simpson, Lisa M and Wall, Ian D and Blaney, Frank E and Reynolds, Christopher A (2011) 'Modeling GPCR active state conformations: The β<sub>2</sub>-adrenergic receptor.' Proteins: Structure, Function, and Bioinformatics, 79 (5). pp. 1441-1457. ISSN 0887-3585

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The recent publication of several G protein-coupled receptor (GPCR) structures has increased the information available for homology modeling inactive class A GPCRs. Moreover, the opsin crystal structure shows some active features. We have therefore combined information from these two sources to generate an extensively validated model of the active conformation of the β 2-adrenergic receptor. Experimental information on fully active GPCRs from zinc binding studies, site-directed spin labeling, and other spectroscopic techniques has been used in molecular dynamics simulations. The observed conformational changes reside mainly in transmembrane helix 6 (TM6), with additional small but significant changes in TM5 and TM7. The active model has been validated by manual docking and is in agreement with a large amount of experimental work, including site-directed mutagenesis information. Virtual screening experiments show that the models are selective for β-adrenergic agonists over other GPCR ligands, for (R)- over (S)-β-hydroxy agonists and for β 2-selective agonists over β 1-selective agonists. The virtual screens reproduce interactions similar to those generated by manual docking. The C-terminal peptide from a model of the stimulatory G protein, readily docks into the active model in a similar manner to which the C-terminal peptide from transducin, docks into opsin, as shown in a recent opsin crystal structure. This GPCR-G protein model has been used to explain site-directed mutagenesis data on activation. The agreement with experiment suggests a robust model of an active state of the β 2-adrenergic receptor has been produced. The methodology used here should be transferable to modeling the active state of other GPCRs. © 2011 Wiley-Liss, Inc.

Item Type: Article
Uncontrolled Keywords: restrained molecular dynamics; docking; virtual screening; agonist; muscarinic receptor; selectivity; rigid core analysis; principle component analysis
Subjects: Q Science > QH Natural history > QH301 Biology
Divisions: Faculty of Science and Health
Faculty of Science and Health > Life Sciences, School of
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 04 Aug 2011 15:06
Last Modified: 18 Aug 2022 11:14

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