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The role of helices 5 and 6 on the human β 1 -adrenoceptor activation mechanism

2011; Taylor & Francis; Volume: 38; Issue: 3 Linguagem: Inglês

10.1080/08927022.2011.616501

1029-0435

Lucas Villas Bôas Hoelz, André A. S. T. Ribeiro, Rafael C. Bernardi, Bruno A. C. Horta, Magaly Girão Albuquerque, Fernando Moreira da Silva, Pedro G. Pascutti, Ricardo Bicca de Alencastro,

Neuropeptides and Animal Physiology

Abstract The human β1-adrenoceptor (β1AR) is a G-protein-coupled receptor (GPCR) involved in sympathetic system regulation through agonist-induced activation. The conserved CWXP-motif in helix 6 (rotamer toggle switch) is one of the most important activation switches in Class A GPCRs. In order to investigate how the agonist binding disturbs this switch, we carried out molecular dynamics simulations of a hβ1AR model in the apo and R-noradrenaline-bound forms. The results show that the agonist binding changes the β1-angle distribution of Cys336, Trp337 and Phe341 residues and increases the helix 6 bending. Overall, we provide a functional hβ1AR model, showing how the rotamer toggle switch mechanism works at atomic level. Keywords: human β1-adrenoceptorrotamer toggle switchmolecular dynamics Acknowledgements The authors would like to thank the Brazilian agencies CNPq, FAPERJ and CAPES for financial support. Notes 1. Residues are numbered according to their positions in the hβ1 AR sequence, e.g. Asp138. We also numbered conserved residues relative to the TM and the position in which it is located, e.g. Asp3.32, TM3 at position 32 [Citation6].