Functional Role of the “Ionic Lock”—An Interhelical Hydrogen-Bond Network in Family A Heptahelical Receptors

Vogel, Reiner; Mahalingam, Mohana; Lüdeke, Steffen; Huber, Thomas; Siebert, Friedrich; Sakmar, Thomas P.

doi:10.1016/j.jmb.2008.05.022

Cited by 152 publications

(176 citation statements)

References 41 publications

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“…The deprotonation of the Schiff base is a prerequisite characteristic for the Meta II state and precedes structural changes known from FTIR and EPR spectroscopic data [53,71,72,73,77,80,81,92,93,133,135]. The transition to the active state of rhodopsin is then accompanied by multiple structural alterations, comprising the breakage of the "ionic lock", rearrangement of the NPxxY(x) 5,6 F microdomain, changes in protonation switches, i.e.…”

Section: Sequential Activation Process Of Rhodopsinmentioning

confidence: 98%

“…The E(D)RY motif (in TM3) is part of a hydrogen bonded network -the so-called "ionic lock" [51,52,53,54] -which tethers Arg-135 (on TM3) to Glu-247 (on TM6). A second motif, the NPxxY(x) 5,6 F motif links Tyr-306 (on TM7) and Phe-313 (on H8).…”

Section: Structure Of Rhodopsinmentioning

confidence: 99%

“…These two salt bridges are part of a more extended hydrogen bonded network between Glu-134, Arg-135, Glu-247 and Thr-251, the so-called "ionic lock", which links the cytoplasmic segments of TM3 and TM6 (Figure 3.7B) [31,47]. In the course of rhodopsin activation and breakage of the "ionic lock", proton uptake occurs which is abolished when Glu-134 is replaced by glutamine [53,72,81,94].…”

Section: Helix Movements In Low Ph Opsinmentioning

confidence: 99%

“…In the course of rhodopsin activation, proton transfer from the retinal Schiff base to its counterion, Glu-113, and proton uptake by Glu-134 as proton acceptor or mediator occur sequentially [53,72,81,94].…”

Section: Constitutively Active Mutants Of Rhodopsinmentioning

confidence: 99%

“…and Phe 7.60 , respectively. Protein structural alterations and release of the constraints are induced by cis/trans isomerization of the chromophore following light absorption [51,52,53,54,77,129,130]. Due to retinal isomerization, the stabilizing salt bridge present in the inactive rhodopsin ground state between the protonated 11-cis-retinal Schiff base and the Glu-113 (on TM3) counterion is broken [25,31,58].…”

Section: Sequential Activation Process Of Rhodopsinmentioning

confidence: 99%

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Crystal structure of the ligand-free G-protein-coupled receptor opsin

Park

Scheerer

Hofmann

et al. 2008

Nature

842

925

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Compared with the known structure of inactive rhodopsin, opsin displays prominent structural changes in the conserved E(D)RY and NPxxY(x) 5,6 F regions and TM5-TM7. At the cytoplasmic side, TM6 is tilted outwards by 6-7 Å, whereas the helix structure of TM5 is more elongated and close to TM6. These structural changes, of which some are attributed to an active GPCR state, reorganize the empty retinal binding pocket to disclose two openings for exit and entry of retinal. The opsin structure thus sheds new light on binding of hydrophobic ligands to GPCRs, GPCR activation and signal transfer to the G protein.

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Section: Sequential Activation Process Of Rhodopsinmentioning

confidence: 98%

Section: Structure Of Rhodopsinmentioning

confidence: 99%

Section: Helix Movements In Low Ph Opsinmentioning

confidence: 99%

Section: Constitutively Active Mutants Of Rhodopsinmentioning

confidence: 99%

Section: Sequential Activation Process Of Rhodopsinmentioning

confidence: 99%

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Crystal structure of the ligand-free G-protein-coupled receptor opsin

Park

Scheerer

Hofmann

et al. 2008

Nature

842

925

View full text Add to dashboard Cite

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Activation of Class B GPCR by Peptide Ligands: General Structural Aspects

Ernicke¹,

Coin²

2022

GPCRs as Therapeutic Targets

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A Usual G‐Protein‐Coupled Receptor in Unusual Membranes

et al. 2015

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G-protein-coupled receptors (GPCRs) are the largest family of membrane-bound receptors and constitute ~50% of all known drug targets. They offer great potential for membrane protein nanotechnologies. We report here a charge-interaction-directed reconstitution mechanism that induces spontaneous insertion of bovine rhodopsin, the eukaryotic GPCR, into both lipid-and polymer-based artificial membranes. We reveal a new allosteric mode of rhodopsin activation incurred by the non-biological membranes: the cationic membrane drives a transition from inactive MI to activated MII state in the absence of high [H + ] or negative spontaneous curvature. We attribute this activation to the attractive charge interaction between the membrane surface and the deprotonated Glu134 residue of the rhodopsin-conserved ERY sequence motif that helps break the cytoplasmic "ionic lock". This study unveils a novel design concept of non-biological membranes to reconstitute and harness GPCR functions in synthetic systems. Graphical AbstractMembrane-embedded rhodopsin (left) in dark state (1U19; blue) overlaid with its activated MII state (3PXO; yellow). The cytoplasmic "ionic lock" (i.e. Glu134-Arg135 salt bridge) in the dark state (top right) is broken by attractive charge interactions between the cationic membrane surface

show abstract

Functional Role of the “Ionic Lock”—An Interhelical Hydrogen-Bond Network in Family A Heptahelical Receptors

Cited by 152 publications

References 41 publications

Crystal structure of the ligand-free G-protein-coupled receptor opsin

Crystal structure of the ligand-free G-protein-coupled receptor opsin

Activation of Class B GPCR by Peptide Ligands: General Structural Aspects

A Usual G‐Protein‐Coupled Receptor in Unusual Membranes

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