The structural basis of g-protein-coupled receptor function and dysfunction in human diseases

Schöneberg, Torsten; Schulz, Angela; Gudermann, Thomas

doi:10.1007/bfb0116587

Cited by 46 publications

(49 citation statements)

References 401 publications

(282 reference statements)

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“…With the exception of the glycoprotein hormone receptors, ligand binding is thought to occur in the extracellular portion of the transmembrane helix bundle and does not involve the N terminus that is generally shorter than in the other GPCR families. Rhodopsin-like GPCR feature a conserved TM core with typical E/DRY and N/DP(X)nY motifs on the border of TM3 and ICL2 and TM7, respectively, that are present in almost all members of this family (for more details on conserved structural determinants see [56]). GPCR with this signature are identified in all bilateria but also in cnidaria which implies that rhodopsin-like GPCR evolved before the protostome-deuterostome split, 570-700 Myr ago.…”

Section: Evolution Of the Five Gpcr Familiesmentioning

confidence: 99%

Evolution of GPCR: Change and continuity

Strotmann

Schröck

Böselt

et al. 2011

Molecular and Cellular Endocrinology

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Once introduced into the very early eukaryotic blueprint, seven-transmembrane receptors soon became the central and versatile components of the evolutionary highly successful G protein-coupled transmembrane signaling mechanism. In contrast to all other components of this signal transduction pathway, G protein-coupled receptors (GPCR) evolved in various structural families, eventually comprising hundreds of members in vertebrate genomes. Their functional diversity is in contrast to the conserved transmembrane core and the invariant set of intracellular signaling mechanisms, and it may be the interplay of these properties that is the key to the evolutionary success of GPCR. The GPCR repertoires retrieved from extant vertebrate genomes are the recent endpoints of this long evolutionary process. But the shaping of the fine structure and the repertoire of GPCR is still ongoing, and signatures of recent selection acting on GPCR genes can be made visible by modern population genetic methods. The very dynamic evolution of GPCR can be analyzed from different perspectives: at the levels of sequence comparisons between species from different families, orders and classes, and at the level of populations within a species. Here, we summarize the main conclusions from studies at these different levels with a specific focus on the more recent evolutionary dynamics of GPCR.

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Section: Evolution Of the Five Gpcr Familiesmentioning

confidence: 99%

Evolution of GPCR: Change and continuity

Strotmann

Schröck

Böselt

et al. 2011

Molecular and Cellular Endocrinology

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“…Following the rigid-body dynamics, loops were added to the helices by using WHATIF software (35). We then identified the possible disulfide linkages among the conserved cysteines across all GPCRs (36,37) and added disulfide bonds where there are close in the predicted structure. It is plausible to consider the disulfide linkages among conserved cysteines in the TM region earlier in the protocol, but the disulfide linkages among the loops are added at this step to constrain the loop conformation.…”

mentioning

confidence: 99%

Prediction of structure and function of G protein-coupled receptors

Vaidehi

Floriano

Trabanino

et al. 2002

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

278

258

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G protein-coupled receptors (GPCRs) mediate our sense of vision, smell, taste, and pain. They are also involved in cell recognition and communication processes, and hence have emerged as a prominent superfamily for drug targets. Unfortunately, the atomic-level structure is available for only one GPCR (bovine rhodopsin), making it difficult to use structure-based methods to design drugs and mutation experiments. We have recently developed first principles methods (MembStruk and HierDock) for predicting structure of GPCRs, and for predicting the ligand binding sites and relative binding affinities. Comparing to the one case with structural data, bovine rhodopsin, we find good accuracy in both the structure of the protein and of the bound ligand. We report here the application of MembStruk and HierDock to ␤1-adrenergic receptor, endothelial differential gene 6, mouse and rat I7 olfactory receptors, and human sweet receptor. We find that the predicted structure of ␤1-adrenergic receptor leads to a binding site for epinephrine that agrees well with the mutation experiments. Similarly the predicted binding sites and affinities for endothelial differential gene 6, mouse and rat I7 olfactory receptors, and human sweet receptor are consistent with the available experimental data. These predicted structures and binding sites allow the design of mutation experiments to validate and improve the structure and function prediction methods. As these structures are validated they can be used as targets for the design of new receptor-selective antagonists or agonists for GPCRs.GPCR ͉ olfactory receptor ͉ ␤-adrenergic receptor ͉ endothelial differentiation gene ͉ taste receptor G protein-coupled receptors (GPCRs) mediate senses such as odor, taste, vision, and pain (1) in mammals. In addition, important cell recognition and communication processes often involve GPCRs. Indeed, many diseases involve malfunction of these receptors (2), making them important targets for drug development. Unfortunately, despite their importance there is insufficient structural information on GPCRs for structure-based drug design. This is because these membrane-bound proteins are difficult to crystallize, and the atomic-level structure has been solved only for bovine rhodopsin (3, 4). Consequently, it is important to develop theoretical methods to predict the structure and function of GPCRs (5, 6).Experimental data relevant to the function of GPCRs is available for ligand activation of GPCRs (7-15) and site-directed mutagenesis (16)(17)(18). This data has led to information about structural features in the ligand-binding regions of GPCRs (refs. 5 and 19, and references therein). Protein sequence analyses on GPCRs reveals a common protein topology consisting of a membrane-spanning seven-helix bundle, which likely accommodates the binding site for low-molecular-weight ligands. Structurally, GPCRs can be classified as (i) GPCRs with short N terminus (5-80 residues) and (ii) GPCRs with a long N-terminal ectodomain (Ϸ80-600 residues). The long N terminus of ...

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“…As a consequence, many major diseases, such as hypertension, cardiac dysfunction, depression, anxiety, obesity, inflammation, and pain, involve malfunction of these receptors (2), making them among the most important drug targets for pharmacological intervention (3)(4)(5). Thus, whereas GPCRs are only a small subset of the human genome, they are the targets for Ϸ50% of all recently launched drugs (6).…”

mentioning

confidence: 99%

G protein-coupled receptors:In silicodrug discovery in 3D

Becker¹,

Marantz²,

Shacham³

et al. 2004

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

164

158

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The application of structure-based in silico methods to drug discovery is still considered a major challenge, especially when the x-ray structure of the target protein is unknown. Such is the case with human G protein-coupled receptors (GPCRs), one of the most important families of drug targets, where in the absence of x-ray structures, one has to rely on in silico 3D models. We report repeated success in using ab initio in silico GPCR models, generated by the PREDICT method, for blind in silico screening when applied to a set of five different GPCR drug targets. More than 100,000 compounds were typically screened in silico for each target, leading to a selection of <100 ''virtual hit'' compounds to be tested in the lab. In vitro binding assays of the selected compounds confirm high hit rates, of 12-21% (full dose-response curves, K i < 5 M). In most cases, the best hit was a novel compound (New Chemical Entity) in the 1-to 100-nM range, with very promising pharmacological properties, as measured by a variety of in vitro and in vivo assays. These assays validated the quality of the hits as lead compounds for drug discovery. The results demonstrate the usefulness and robustness of ab initio in silico 3D models and of in silico screening for GPCR drug discovery.modeling ͉ in silico screening ͉ structure-based G protein-coupled receptors (GPCRs) are membraneembedded proteins, responsible for communication between the cell and its environment (1). As a consequence, many major diseases, such as hypertension, cardiac dysfunction, depression, anxiety, obesity, inflammation, and pain, involve malfunction of these receptors (2), making them among the most important drug targets for pharmacological intervention (3-5). Thus, whereas GPCRs are only a small subset of the human genome, they are the targets for Ϸ50% of all recently launched drugs (6). As targets of paramount importance, it is expected that drug discovery for GPCRs would benefit from the introduction of computational methodologies (7), especially as these methods can be used in conjunction with such experimental methods as high-throughput screening (8, 9), NMR, and crystallography (10).Unfortunately, GPCRs, like other membrane-embedded proteins, have characteristics that make their 3D structure extremely difficult to determine experimentally. To date, the only GPCR for which a 3D structure was determined by x-ray crystallography is bovine rhodopsin (11), which is unique among GPCRs in that its ligand, retinal, is covalently bound and that it responds to light rather than to ligand binding. Hence, in the case of GPCRs, the limited availability of structural data has forced the computational design of ligands to heavily rely on ligand-based techniques. Indeed, for many GPCRs, the natural ligand can provide a good starting point, leading to useful pharmacophore models that can be used for identifying lead structures with novel scaffolds (6). These methods have been successfully applied for the discovery of peptide agonists to the somatostatin receptor (12) and for...

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The structural basis of g-protein-coupled receptor function and dysfunction in human diseases

Cited by 46 publications

References 401 publications

Evolution of GPCR: Change and continuity

Evolution of GPCR: Change and continuity

Prediction of structure and function of G protein-coupled receptors

G protein-coupled receptors:In silicodrug discovery in 3D

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