Description: Structural Mechanisms of Voltage Sensing in G Protein-Coupled Receptors

This title appears in the Scientific Report : 2016

Structural Mechanisms of Voltage Sensing in G Protein-Coupled Receptors

G-protein-coupled receptors (GPCRs) form the largest superfamily of membrane proteins and one-third of all drug targets in humans. A number of recent studies have reported evidence for substantial voltage regulation of GPCRs. However, the structural basis of GPCR voltage sensing has remained enigmat...

Personal Name(s):	Vickery, Owen N.
	Machtens, Jan-Philipp / Tamburrino, Giulia / Seeliger, Daniel / Zachariae, Ulrich (Corresponding author)
Contributing Institute:	JARA - HPC; JARA-HPC Zelluläre Biophysik; ICS-4
Published in:	Structure, 24 (2016) 6, S. 997 - 1007
Imprint:	London [u.a.] Elsevier Science 2016
DOI:	10.1016/j.str.2016.04.007
PubMed ID:	27210286
Document Type:	Journal Article
Research Program:	MOLECULAR MODELLING OF BIFUNCTIONAL MEMBRANE TRANSPORT PROTEINS Engineering Cell Function
Link:	OpenAccess OpenAccess
	Publikationsportal JuSER

Please use the identifier: http://dx.doi.org/10.1016/j.str.2016.04.007 in citations.
Please use the identifier: http://hdl.handle.net/2128/11948 in citations.

G-protein-coupled receptors (GPCRs) form the largest superfamily of membrane proteins and one-third of all drug targets in humans. A number of recent studies have reported evidence for substantial voltage regulation of GPCRs. However, the structural basis of GPCR voltage sensing has remained enigmatic. Here, we present atomistic simulations on the δ-opioid and M2 muscarinic receptors, which suggest a structural and mechanistic explanation for the observed voltage-induced functional effects. The simulations reveal that the position of an internal Na+ ion, recently detected to bind to a highly conserved aqueous pocket in receptor crystal structures, strongly responds to voltage changes. The movements give rise to gating charges in excellent agreement with previous experimental recordings. Furthermore, free energy calculations show that these rearrangements of Na+ can be induced by physiological membrane voltages. Due to its role in receptor function and signal bias, the repositioning of Na+ has important general implications for signal transduction in GPCRs.