GPCRdb: an information system for G protein-coupled receptors

Horn, Florence; Bettler, Emmanuel; Oliveira, Laerte; Campagne, Fabien; Cohen, Fred E.; Vriend, Gerrit

doi:10.1093/nar/gkv1178

Cited by 510 publications

(286 citation statements)

References 47 publications

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“…Early sequence analysis revealed that CB 1 has a moderate sequence identity with LPA 1 (13% overall, 28% in TM regions) and S1P 1 (14% overall, 27% in TM regions) (Bramblett et al, 1995; Isberg et al, 2016) (Figure S5). Crystal structures of LPA 1 (Chrencik et al, 2015) and S1P 1 (Hanson et al, 2012) have been recently determined.…”

Section: Resultsmentioning

confidence: 99%

Crystal Structure of the Human Cannabinoid Receptor CB1

Hua

Vemuri

et al. 2016

Cell

503

488

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SUMMARY Cannabinoid receptor 1 (CB1) is the principal target of Δ9-tetrahydrocannabinol (THC), a psychoactive chemical from Cannabis sativa with a wide range of therapeutic applications and a long history of recreational use. CB1 is activated by endocannabinoids, and is a promising therapeutic target for pain management, inflammation, obesity and substance abuse disorders. Here, we present the 2.8 Å crystal structure of human CB1 in complex with AM6538, a stabilizing antagonist, synthesized and characterized for this structural study. The structure of the CB1-AM6538 complex reveals key features of the receptor and critical interactions for antagonist binding. In combination with functional studies and molecular modeling, the structure provides insight into the binding mode of naturally occurring CB1 ligands, such as THC, and synthetic cannabinoids. This enhances our understanding of the molecular basis for the physiological functions of CB1 and provides new opportunities for the design of next-generation CB1-targeting pharmaceuticals.

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Section: Resultsmentioning

confidence: 99%

Crystal Structure of the Human Cannabinoid Receptor CB1

Hua

Vemuri

et al. 2016

Cell

503

488

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“…A first search focused on a set of 15 generic peptide receptor-ligand interacting residue positions annotated from all eight crystallized peptide GPCRs available at the time (Isberg et al., 2016). A second search involved all class A GPCR 44 accessible binding pocket residues (Gloriam et al., 2009).…”

Section: Methodsology and Experimental Proceduresmentioning

confidence: 99%

“…Abbreviations: I% = percent sequence identity, S% = percent sequence similarity, S = similarity score. The alignment was made in GPCRdb (Isberg et al., 2016). Residue numbering is according to GPCRdb numbering system (Isberg et al., 2015).…”

Section: Figmentioning

confidence: 99%

The orphan G protein-coupled receptor GPR139 is activated by the peptides: Adrenocorticotropic hormone (ACTH), α-, and β-melanocyte stimulating hormone (α-MSH, and β-MSH), and the conserved core motif HFRW

Nøhr

Shehata

Hauser

et al. 2017

Neurochemistry International

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GPR139 is an orphan G protein-coupled receptor that is expressed primarily in the brain. Not much is known regarding the function of GPR139. Recently we have shown that GPR139 is activated by the amino acids l-tryptophan and l-phenylalanine (EC50 values of 220 μM and 320 μM, respectively), as well as di-peptides comprised of aromatic amino acids. This led us to hypothesize that GPR139 may be activated by peptides. Sequence alignment of the binding cavities of all class A GPCRs, revealed that the binding pocket of the melanocortin 4 receptor is similar to that of GPR139. Based on the chemogenomics principle “similar targets bind similar ligands”, we tested three known endogenous melanocortin 4 receptor agonists; adrenocorticotropic hormone (ACTH) and α- and β-melanocyte stimulating hormone (α-MSH and β-MSH) on CHO-k1 cells stably expressing the human GPR139 in a Fluo-4 Ca2+-assay. All three peptides, as well as their conserved core motif HFRW, were found to activate GPR139 in the low micromolar range. Moreover, we found that peptides consisting of nine or ten N-terminal residues of α-MSH activate GPR139 in the submicromolar range. α-MSH1-9 was found to correspond to the product of a predicted cleavage site in the pre-pro-protein pro-opiomelanocortin (POMC). Our results demonstrate that GPR139 is a peptide receptor, activated by ACTH, α-MSH, β-MSH, the conserved core motif HFRW as well as a potential endogenous peptide α-MSH1-9. Further studies are needed to determine the functional relevance of GPR139 mediated signaling by these peptides.

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“…Models were built using the program Prime 51–53 and using the alignment from GPCRdb for A 2A . 54,55 The hydrogen bond network of the obtained structures was afterward optimized using the Protein Preparation Wizard.…”

Section: Methodsmentioning

confidence: 99%

Relative Binding Free Energy Calculations Applied to Protein Homology Models

Cappel¹,

Hall

Lenselink

et al. 2016

J. Chem. Inf. Model.

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A significant challenge and potential high-value application of computer-aided drug design is the accurate prediction of protein–ligand binding affinities. Free energy perturbation (FEP) using molecular dynamics (MD) sampling is among the most suitable approaches to achieve accurate binding free energy predictions, due to the rigorous statistical framework of the methodology, correct representation of the energetics, and thorough treatment of the important degrees of freedom in the system (including explicit waters). Recent advances in sampling methods and force fields coupled with vast increases in computational resources have made FEP a viable technology to drive hit-to-lead and lead optimization, allowing for more efficient cycles of medicinal chemistry and the possibility to explore much larger chemical spaces. However, previous FEP applications have focused on systems with high-resolution crystal structures of the target as starting points—something that is not always available in drug discovery projects. As such, the ability to apply FEP on homology models would greatly expand the domain of applicability of FEP in drug discovery. In this work we apply a particular implementation of FEP, called FEP+, on congeneric ligand series binding to four diverse targets: a kinase (Tyk2), an epigenetic bromodomain (BRD4), a transmembrane GPCR (A2A), and a protein–protein interaction interface (BCL-2 family protein MCL-1). We apply FEP+ using both crystal structures and homology models as starting points and find that the performance using homology models is generally on a par with the results when using crystal structures. The robustness of the calculations to structural variations in the input models can likely be attributed to the conformational sampling in the molecular dynamics simulations, which allows the modeled receptor to adapt to the “real” conformation for each ligand in the series. This work exemplifies the advantages of using all-atom simulation methods with full system flexibility and offers promise for the general application of FEP to homology models, although additional validation studies should be performed to further understand the limitations of the method and the scenarios where FEP will work best.

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GPCRdb: an information system for G protein-coupled receptors

Cited by 510 publications

References 47 publications

Crystal Structure of the Human Cannabinoid Receptor CB1

Crystal Structure of the Human Cannabinoid Receptor CB1

The orphan G protein-coupled receptor GPR139 is activated by the peptides: Adrenocorticotropic hormone (ACTH), α-, and β-melanocyte stimulating hormone (α-MSH, and β-MSH), and the conserved core motif HFRW

Relative Binding Free Energy Calculations Applied to Protein Homology Models

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