Beta2 adrenergic receptor activation. Modulation of the proline kink in transmembrane 6 by a rotamer toggle switch - PubMed (original) (raw)

. 2002 Oct 25;277(43):40989-96.

doi: 10.1074/jbc.M206801200. Epub 2002 Aug 6.

Affiliations

Free article

Beta2 adrenergic receptor activation. Modulation of the proline kink in transmembrane 6 by a rotamer toggle switch

Lei Shi et al. J Biol Chem. 2002.

Free article

Abstract

In many rhodopsin-like G-protein-coupled receptors, agonist binding to a cluster of aromatic residues in TM6 may promote receptor activation by altering the configuration of the TM6 Pro-kink and by the subsequent movement of the cytoplasmic end of TM6 away from TM3. We hypothesized that the highly conserved Cys(6.47), in the vicinity of the conserved Pro(6.50), modulates the configuration of the aromatic cluster and the TM6 Pro-kink through specific interactions in its different rotamer configurations. In the beta(2) adrenergic receptor, mutation of Cys(6.47) to Thr, which in an alpha-helix has a different rotamer distribution from Cys and Ser, produced a constitutively active receptor, whereas the Ser mutant was similar to wild-type receptor. Use of the biased Monte Carlo technique of Conformational Memories showed that the rotamer changes among Cys/Ser/Thr(6.47), Trp(6.48), and Phe(6.52) are highly correlated, representing a rotamer "toggle switch" that may modulate the TM6 Pro-kink. Differential modulation of the accessibility of Cys(6.47) and an engineered Cys(6.52) in wild type and a constitutively active background provides experimental support for the association of this rotamer switch with receptor activation.

PubMed Disclaimer

Similar articles

Cited by

Publication types

MeSH terms

Substances

LinkOut - more resources