A homology modeling study toward the understanding of three-dimensional structure and putative pharmacological profile of the G-protein coupled receptor GPR55.
Source
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, 800 E. Leigh Street, Richmond, VA 23219-1540, USA.
Abstract
The orphan G-protein coupled receptor GPR55 was shown to bind to certain cannabinoid compounds which led to its initial classification as the third type of cannabinoid receptor. Later studies showed that lysophosphatidylinositol (LPI) also activated GPR55, in particular 2-arachidonoyl-LPI was proposed to be its endogenous ligand. However, the results of pharmacological studies regarding GPR55 have been quite inconsistent. Despite its contradictory pharmacological profile, GPR55 has been implicated in various disease states including inflammatory and neuropathic pain, metabolic bone diseases, and cancer. Herein, we report the ligand binding properties of GPR55 by applying homology modeling and automated docking algorithms in order to understand its pharmacological profile. The 3D homology model of GPR55 was built based on the adenosine A(2A) receptor crystal structure. Docking studies of several types of reported ligands were carried out afterwards. The results indicated that both hydrogen bonding and hydrophobic interactions contributed significantly for its ligand binding and the amino acid residue Lys80 seemed to be the anchor residue for receptor recognition. In addition, its putative agonist and antagonist appeared to recognize different domains of the receptor corresponding to their reported pharmacological activities.
Copyright © 2012 Elsevier Inc. All rights reserved.
Copyright © 2012 Elsevier Inc. All rights reserved.
- PMID:
23220281
[PubMed – indexed for MEDLINE]
Publication Types, MeSH Terms, Substances, Grant Support
Publication Types
MeSH Terms
- Amino Acid Sequence
- Animals
- Carotenoids/chemistry
- Catalytic Domain
- Cattle
- Humans
- Ligands
- Models, Molecular*
- Molecular Docking Simulation
- Molecular Sequence Data
- Protein Binding
- Protein Conformation
- Protein Interaction Domains and Motifs
- Receptor, Adenosine A2A/chemistry
- Receptors, Adrenergic, beta-2/chemistry
- Receptors, G-Protein-Coupled/chemistry*
- Sequence Alignment
Substances
- GPRC5C protein, human
- Ligands
- Receptor, Adenosine A2A
- Receptors, Adrenergic, beta-2
- Receptors, G-Protein-Coupled
- rhodopin
- Carotenoids
Grant Support
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Full Text Sources
Graphical abstract
GPR55 antagonist CBD binding mode in the GPR55 homology model.
Highlight
► We constructed the homology model of the orphan G-protein coupled receptor GPR55. ► A number of reported ligands were docked into the homology model of the receptor. ► Ligand binding sites were characterized and analyzed. ► Critical anchor amino acid residue was identified. ► Putative agonist and antagonist binding pockets were discussed.
Keywords
- GPR55;
- G-protein coupled receptors;
- Homology modeling;
- Automated docking
Figures and tables from this article:
- Fig. 1. Sequence alignment of bovine rhodopsin (BRHO), LPA receptor subtypes LPA4–6 (LPAR4–6), GPR35, human adenosine A2A receptor (AA2AR), human β2 adrenergic receptor (ADRB2), and GPR5. The Ballesteros–Weinstein numbering system was adopted to mark all the conserved amino acid residues among most of the GPCRs and colored in red. The positively charged amino acid residues that seem to be important for ligand recognition of GPR55 and LPA receptors are colored in blue. The helical range of each helix was marked in general, not a specific manner, in order to represent most of well-known GPCR structures. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
- Fig. 2. Ramachandran plot of the GPR55 homology model.
- Fig. 3. Homology model of GPR55 overlapped with the template crystal structure of human adenosine A2A receptor in ribbon. The GPR55 model is presented in cyan and the adenosine A2A model is in magenta. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
- Fig. 4. Ligands used in the docking study shown with EC50 values for the reported agonists and the reported IC50 value for the antagonist CBD.
- Fig. 5. The binding modes of CBD (A), 2-arachidonoyl LPI (B), Δ9-THC (C), AM-281 (D), anandamide (E), 2-AG (F) in the homology model of GPR55.
- Fig. 6. Comparison of binding modes of GPR55 antagonist CBD (A) and agonist 2-arachidonoyl LPI (B). Amino acid residues that are found to be important for GPR55 ligand recognition is shown in purple. Phe239 which is thought to be involved in GPR55 activation is colored in green.
- Table 1. Sequence comparison of GPR55 with the bovine rhodopsin, the human β2 adrenergic receptor, and the human adenosine A2A receptor.
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- Table 2. Top GoldScores of docked ligands.
- View Within Article
- Corresponding author.
Copyright © 2012 Elsevier Inc. All rights reserved.
