Research Repository

Structural and functional roles of small group-conserved amino acids present on helix-H7 in the β2-adrenergic receptor

Arakawa, Makoto and Chakraborty, Raja and Upadhyaya, Jasbir and Eilers, Markus and Reeves, Philip J and Smith, Steven O and Chelikani, Prashen (2011) 'Structural and functional roles of small group-conserved amino acids present on helix-H7 in the β2-adrenergic receptor.' Biochimica et Biophysica Acta (BBA) - Biomembranes, 1808 (4). pp. 1170-1178. ISSN 0005-2736

Full text not available from this repository.


Sequence analysis of the class A G protein-coupled receptors (GPCRs) reveals that most of the highly conserved sites are located in the transmembrane helices. A second level of conservation exists involving those residues that are conserved as a group characterized by small and/or weakly polar side chains (Ala, Gly, Ser, Cys, Thr). These positions can have group conservation levels of up to 99% across the class A GPCRs and have been implicated in mediating helix-helix interactions in membrane proteins. We have previously shown that mutation of group-conserved residues present on transmembrane helices H2-H4 in the β2-adrenergic receptor (β2-AR) can influence both receptor expression and function. We now target the group-conserved sites, Gly3157.42 and Ser3197.46, on H7 for structure-function analysis. Replacing Ser3197.46 with smaller amino acids (Ala or Gly) did not influence the ability of the mutant receptors to bind to the antagonist dihydroalprenolol (DHA) but resulted in ~ 15-20% agonist-independent activity. Replacement of Ser3197.46 with the larger amino acid leucine lowered the expression of the S319L mutant and its ability to bind DHA. Both the G315A and G315S mutants also exhibited agonist-independent signaling, while the G315L mutant did not show specific binding to DHA. These data indicate that Gly3157.42 and Ser3197.46 are stabilizing β2-AR in an inactive conformation. We discuss our results in the context of van der Waals interactions of Gly3157.42 with Trp286 6.48 and hydrogen bonding interactions of Ser3197.46 with amino acids on H1-H2-H7 and with structural water. © 2011 Elsevier B.V.

Item Type: Article
Uncontrolled Keywords: G-protein coupled receptors (GPCRs); Helix packing; Beta2-adrenergic receptor; GPCR activation; Site-directed mutagenesis
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: 07 Oct 2011 11:48
Last Modified: 18 Aug 2022 11:14

Actions (login required)

View Item View Item