Rhodopsin: Insights from Recent Structural Studies

Sakmar, Thomas P.; Menon, Santosh T.; Marin, Ethan P.; Awad, Elias S.

doi:10.1146/annurev.biophys.31.082901.134348

Cited by 226 publications

(224 citation statements)

References 235 publications

(244 reference statements)

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“…Residue Tyr-136 of the (E/D)RY motif is especially a CA, constitutive activity; LB, ligand binding effects; ME, mechanistic effects observed in structural studies (does not count as functional effect); Exp, decreased expression; G protein, G-protein coupling decreased/completely uncoupled/decreased G-protein stimulation. important in triggering GDP exchange in G proteins (49,50). The generic trigger region extends into the transmembrane area nearly up to the retinal binding pocket in rhodopsin (Fig.…”

Section: Discussionmentioning

confidence: 99%

Evolutionary Trace of G Protein-coupled Receptors Reveals Clusters of Residues That Determine Global and Class-specific Functions

Madabushi

Gross

Philippi

et al. 2004

Journal of Biological Chemistry

185

171

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G protein-coupled receptor (GPCR) activation mediated by ligand-induced structural reorganization of its helices is poorly understood. To determine the universal elements of this conformational switch, we used evolutionary tracing (ET) to identify residue positions commonly important in diverse GPCRs. When mapped onto the rhodopsin structure, these trace residues cluster into a network of contacts from the retinal binding site to the G protein-coupling loops. Their roles in a generic transduction mechanism were verified by 211 of 239 published mutations that caused functional defects. When grouped according to the nature of the defects, these residues subdivided into three striking sub-clusters: a trigger region, where mutations mostly affect ligand binding, a coupling region near the cytoplasmic interface to the G protein, where mutations affect G protein activation, and a linking core in between where mutations cause constitutive activity and other defects. Differential ET analysis of the opsin family revealed an additional set of opsin-specific residues, several of which form part of the retinal binding pocket, and are known to cause functional defects upon mutation. To test the predictive power of ET, we introduced novel mutations in bovine rhodopsin at a globally important position, Leu-79, and at an opsin-specific position, Trp-175. Both were functionally critical, causing constitutive G protein activation of the mutants and rapid loss of regeneration after photobleaching. These results define in GPCRs a canonical signal transduction mechanism where ligand binding induces conformational changes propagated through adjacent trigger, linking core, and coupling regions.The profusion and diversity of G protein-coupled receptors (GPCRs) 1 give them a central role in health and disease. In humans, over 1000 genes encode these receptors (1), each of which responds to a single or few ligands by activating G proteins, which then modulate enzymes and channels to initiate highly amplified signaling cascades. Such cascades control sight, taste, smell, slow neurotransmission and the responses to most water-soluble hormones and chemokines. In fact, GPCRs are so ubiquitous that, although they are the targets of nearly 50% of current drugs (2), this is still a small fraction of their pharmacological potential (3).Some of the major questions relevant to GPCR pharmacology include the following: What residues are critical for ligand binding and G protein activation? What do different receptor families have in common with regard to their activation mechanism? From a structural perspective, it is known that all GPCRs form a seven transmembrane (TM) ␣-helical bundle, connected by three intracellular and three extracellular loops, with an extracellular N terminus and an intracellular C terminus (4, 5). However, low overall sequence identity of 25% even within class A GPCRs (6 -8) suggests that significant deviations can occur in ligand binding pockets and in interhelical contacts that stabilize or mediate the transition between a...

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Section: Discussionmentioning

confidence: 99%

Evolutionary Trace of G Protein-coupled Receptors Reveals Clusters of Residues That Determine Global and Class-specific Functions

Madabushi

Gross

Philippi

et al. 2004

Journal of Biological Chemistry

185

171

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“…7 Important issues for understanding this linkage concern how the conformational change in the retinal, induced by light, is coupled into large-scale conformational changes that ultimately lead to G-protein signaling. 1 Further and closely related questions concern the effects of mutations, the membrane environment, water molecules, and charges.…”

Section: Discussionmentioning

confidence: 99%

“…1,[148][149][150][151][152] How this happens remains a mystery that will require more computational and experimental work. 4,153 The molecular details of how the stable bathorhodopsin intermediate (about 1 ps after light absorption and cis-trans isomerization) leads to conformational changes in the Meta II state were the target of our calculations in this study.…”

Section: Discussionmentioning

confidence: 99%

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How a small change in retinal leads to G‐protein activation: Initial events suggested by molecular dynamics calculations

Stevens

Woolf

2006

Proteins

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Rhodopsin is the prototypical G-protein coupled receptor, coupling light activation with high efficiency to signaling molecules. The dark-state X-ray structures of the protein provide a starting point for consideration of the relaxation from initial light activation to conformational changes that may lead to signaling. In this study we create an energetically unstable retinal in the light activated state and then use molecular dynamics simulations to examine the types of compensation, relaxation, and conformational changes that occur following the cis-trans light activation. The results suggest that changes occur throughout the protein, with changes in the orientation of Helices 5 and 6, a closer interaction between Ala 169 on Helix 4 and retinal, and a shift in the Schiff base counterion that also reflects changes in sidechain interactions with the retinal. Taken together, the simulation is suggestive of the types of changes that lead from local conformational change to light-activated signaling in this prototypical system.

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“…Rhodopsin, the dim light photoreceptor of rod cells, is the best characterized member of the superfamily of G-proteincoupled receptors (GPCRs), 1 (1)(2)(3)(4)(5)(6)(7)(8). Rhodopsin consists of a chain of 348 amino acids, approximately half of which form a cluster of seven membrane-spanning helices located within the membrane (Fig.…”

mentioning

confidence: 99%

Stability of Dark State Rhodopsin Is Mediated by a Conserved Ion Pair in Intradiscal Loop E-2

Janz

Fay

Farrens

2003

Journal of Biological Chemistry

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The rhodopsin crystal structure reveals that intradiscal loop E-2 covers the 11-cis-retinal, creating a "retinal plug." Recently, we noticed the ends of loop E-2 are linked by an ion pair between residues Arg-177 and Asp-190, near the highly conserved disulfide bond. This ion pair appears biologically significant; it is conserved in almost all vertebrate opsins and may occur in other G-protein-coupled receptors. We report here that the Arg-177/Asp-190 ion pair is critical for the folding and stability of dark state rhodopsin. We find ion pair mutants that regenerate with retinal are functionally and spectrally wild-type-like yet thermally unstable in their dark state because of rapid hydrolysis of the retinal Schiff base linkage. Surprisingly, Arrhenius analysis indicates that the activation energies for the hydrolysis process are similar between the ion pair mutants and wild-type rhodopsin. Furthermore, the ion pair mutants do not show increased reactivity toward hydroxylamine, suggesting that their instability is not caused by an increased exposure to bulk solvent. Our results indicate that the loop E-2 ion pair is important for rhodopsin stability and thus suggest that retinitis pigmentosa observed in patients with Asp-190 mutations may in part be the result of thermally unstable rhodopsin proteins.

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Rhodopsin: Insights from Recent Structural Studies

Cited by 226 publications

References 235 publications

Evolutionary Trace of G Protein-coupled Receptors Reveals Clusters of Residues That Determine Global and Class-specific Functions

Evolutionary Trace of G Protein-coupled Receptors Reveals Clusters of Residues That Determine Global and Class-specific Functions

How a small change in retinal leads to G‐protein activation: Initial events suggested by molecular dynamics calculations

Stability of Dark State Rhodopsin Is Mediated by a Conserved Ion Pair in Intradiscal Loop E-2

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