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. DOI https://doi.org/10.1002/prot.22974
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. DOI https://doi.org/10.1002/prot.22974
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. DOI https://doi.org/10.1002/prot.22974
Abstract
<jats:title>Abstract</jats:title><jats:p>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<jats:sub>2</jats:sub>‐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 (<jats:italic>R</jats:italic>)‐ over (<jats:italic>S</jats:italic>)‐β‐hydroxy agonists and for β<jats:sub>2</jats:sub>‐selective agonists over β<jats:sub>1</jats:sub>‐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<jats:sub>2</jats:sub>‐adrenergic receptor has been produced. The methodology used here should be transferable to modeling the active state of other GPCRs. Proteins 2011. © 2011 Wiley‐Liss, Inc.</jats:p>
Item Type: | Article |
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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: | Unnamed user with email elements@essex.ac.uk |
Depositing User: | Unnamed user with email elements@essex.ac.uk |
Date Deposited: | 04 Aug 2011 15:06 |
Last Modified: | 07 Aug 2024 19:51 |
URI: | http://repository.essex.ac.uk/id/eprint/346 |