Three-dimensional representations of G protein-coupled receptor structures and mechanisms

Visiers, Irache; Ballesteros, Juan A.; Weinstein, Harel

doi:10.1016/s0076-6879(02)43145-x

Cited by 184 publications

(275 citation statements)

References 128 publications

Supporting

Mentioning

260

Contrasting

Order By: Relevance

“…Although earlier work that relied upon indirect methods such as EPR, Cys cross-linking, and fluorescence predicted that there are large rigid body movements of the transmembrane helices upon attainment of the Meta II state (11,17,21) the scale of movements we predict based on the photoactivated crystal structure is much smaller. This finding is not altogether surprising as analysis of the structural changes upon activation of the phototaxic archeal protein bacteriorhodopsin were predicted to be much larger when measured via indirect biochemical methods than what was seen in the activated crystal structure (22).…”

Section: Discussioncontrasting

confidence: 53%

“…The dimer is stabilized through three symmetric contact patches consisting of a hydrophobic interaction at the top of helix I centered at Met-49 ( Fig. 2 A Left Inset), or 1.34 in nomenclature for GPCRs (17), polar interactions between Tyr-96 (2.63) and His-100 (2.67) (Fig. 2 A Right Inset), and hydrophobic interactions at the C terminus that may involve the palmitoylate groups on C322 and C323 (data not shown).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Crystal structure of a photoactivated deprotonated intermediate of rhodopsin

Salom

Lodowski

Stenkamp

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

420

466

View full text Add to dashboard Cite

The changes that lead to activation of G protein-coupled receptors have not been elucidated at the structural level. In this work we report the crystal structures of both ground state and a photoactivated deprotonated intermediate of bovine rhodopsin at a resolution of 4.15 Å. In the photoactivated state, the Schiff base linking the chromophore and Lys-296 becomes deprotonated, reminiscent of the G protein-activating state, metarhodopsin II. The structures reveal that the changes that accompany photoactivation are smaller than previously predicted for the metarhodopsin II state and include changes on the cytoplasmic surface of rhodopsin that possibly enable the coupling to its cognate G protein, transducin. Furthermore, rhodopsin forms a potentially physiologically relevant dimer interface that involves helices I, II, and 8, and when taken with the prior work that implicates helices IV and V as the physiological dimer interface may account for one of the interfaces of the oligomeric structure of rhodopsin seen in the membrane by atomic force microscopy. The activation and oligomerization models likely extend to the majority of other G protein-coupled receptors.G protein-coupled receptor ͉ G protein-coupled receptor activation ͉ phototransduction ͉ membrane protein structure G protein-coupled receptors (GPCRs) comprise the largest family of transmembrane receptors in animals, accounting for Ϸ3% of the genome (1). GPCRs are involved in detecting a large variety of chemical and physical signals, and they are the targets of Ϸ50% of current therapeutics. Structural information on GPCRs has been limited because of difficulties with their expression, purification, intrinsic chemical heterogeneity, and instability. These biochemical problems were overcome by using rhodopsin as a model GPCR, as it is highly expressed in a homogeneous form in rod photoreceptors and stabilized in the ground state by its covalently bound chromophore, 11-cis-retinal (2).The first crystal structure of rhodopsin revealed the arrangement of helices, the interhelical connections, the chromophore binding site, the extracellular ''plug,'' interactions involved in ligand binding in other GPCRs, and cytoplasmic helix 8 (3). Further improvements in the rhodopsin crystals yielded higher-resolution diffraction data that provided details about the effects of water molecules located close to the chromophore and more precise descriptions of the cytoplasmic loops. However, the improved crystals did not elucidate the mechanism of activation (4, 5). The arrangement of the seven transmembrane helices of rhodopsin differs from that in the more completely structurally studied bacterial retinoid-binding protein, bacteriorhodopsin (6).Upon absorption of a single photon of light, rhodopsin's chromophore, 11-cis-retinal, isomerizes to form all-trans-retinal, a covalently bound, full agonist. Once all-trans-retinal is formed, the protein portion of rhodopsin progresses through a series of photostates, including bathorhodopsin, lumirhodopsin, and metarhodopsin I (Met...

show abstract

Section: Discussioncontrasting

confidence: 53%

Section: Resultsmentioning

confidence: 99%

Crystal structure of a photoactivated deprotonated intermediate of rhodopsin

Salom

Lodowski

Stenkamp

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

420

466

View full text Add to dashboard Cite

show abstract

“…Previous studies have shown that strongly conserved positions such as C3.25, R3.50, and W6.48 (numbering scheme according to Ballesteros and Weinstein 26 ) are involved in receptor folding and activation. 3,16,35,[45][46][47][48] Our approach puts more emphasis on discriminating between the binding sites of class A GPCRs and the other two categories. It aims to cluster residues according to their function based on two assumptions.…”

Section: Discussionmentioning

confidence: 99%

“…The binding site of bovine rhodopsin was taken from the crystal structure 1GZM, then mapped onto both the two-entropies plot and the entropy-variability plot, as shown in Figure 4. The residues within 4 Å distance of retinal in the crystal structure 1GZM are as follows: E113 (3.28), A117 (3.32), T118 (3.33), G121 (3. matic cluster" before by Visiers et al 35 According to the authors, once the ligand is recognized by subfamilyspecific residues and occupies the binding region, the aromatic cluster will be disturbed and respond through concerted conformational rearrangements of the aromatic side-chains to promote receptor activation toward the cytoplasmic side of the receptor. It is safe to conclude that this conserved "aromatic cluster" makes no contribution to the specificity of endogenous ligand binding, but that it is responsible for a general activation mechanism [arrow pointing to "common activation mechanism" in Fig.…”

Section: Separating Positions In the Ligand-binding Site From Other Pmentioning

confidence: 99%

A two‐entropies analysis to identify functional positions in the transmembrane region of class A G protein‐coupled receptors

Lameijer

Beukers

et al. 2006

Proteins

View full text Add to dashboard Cite

Residues in the transmembrane region of G protein-coupled receptors (GPCRs) are important for ligand binding and activation, but the function of individual positions is poorly understood. Using a sequence alignment of class A GPCRs (grouped in subfamilies), we propose a so-called "two-entropies analysis" to determine the potential role of individual positions in the transmembrane region of class A GPCRs. In our approach, such positions appear scattered, while largely clustered according to their biological function. Our method appears superior when compared to other bioinformatics approaches, such as the evolutionary trace method, entropy-variability plot, and correlated mutation analysis, both qualitatively and quantitatively.

show abstract

“…Figure 2 highlights regions that are predicted as TMs by two transmembrane prediction algorithms: TMHMM 32 and HMMTOP 33 TM. Both were identified as the best -helical TM prediction programs in an analysis of over ten such programs 34 .…”

Section: Tagtaggtgtagtaaagttgataatgaaatatcactctaaa Tcagtgg Cttaamentioning

confidence: 99%

An Olfactory Receptor Pseudogene whose Function emerged in Humans

Lai

Bahl

Gremigni³

et al. 2007

Nat Prec

View full text Add to dashboard Cite

Human olfactory receptor, hOR17-210, is identified as a pseudogene in the human genome. Experimental data has shown however, that the gene product of cloned hOR17-210 cDNA was able to bind an odorant-binding protein and is narrowly tuned for excitation by cyclic ketones. Supported by experimental results, we used the bioinformatics methods of sequence analysis, computational protein modeling and docking, to show that functionality in this receptor is retained due to sequence-structure features not previously observed in mammalian ORs. This receptor does not possess the first two transmembrane helical domains (of seven typically seen in GPCRs). It however, possesses an additional TM that has not been observed in other human olfactory receptors. By incorporating these novel structural features, we created two putative models for this receptor. We also docked odor ligands that were experimentally shown to bind hOR17-210 model. We show how and why structural modifications of OR17-210 do not hinder this receptor's functionality. Our studies reveal that novel gene rearrangement that result in sequence and structural diversity in has a bearing on OR and GPCR function and evolution.

show abstract

Three-dimensional representations of G protein-coupled receptor structures and mechanisms

Cited by 184 publications

References 128 publications

Crystal structure of a photoactivated deprotonated intermediate of rhodopsin

Crystal structure of a photoactivated deprotonated intermediate of rhodopsin

A two‐entropies analysis to identify functional positions in the transmembrane region of class A G protein‐coupled receptors

An Olfactory Receptor Pseudogene whose Function emerged in Humans

Contact Info

Product

Resources

About