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http://dx.doi.org/10.7314/APJCP.2013.14.12.7473

Computational Analysis of the 3-D structure of Human GPR87 Protein: Implications for Structure-Based Drug Design  

Rani, Mukta (Department of Pharmacology and Therapeutics, King George’s Medical University, (Erstwhile C.S.M. Medical University))
Nischal, Anuradha (Department of Pharmacology and Therapeutics, King George’s Medical University, (Erstwhile C.S.M. Medical University))
Sahoo, Ganesh Chandra (Biomedical Informatics Centre, Rajendra Memorial Research Institute of Medical Sciences)
Khattri, Sanjay (Department of Pharmacology and Therapeutics, King George’s Medical University, (Erstwhile C.S.M. Medical University))
Publication Information
Asian Pacific Journal of Cancer Prevention / v.14, no.12, 2013 , pp. 7473-7482 More about this Journal
Abstract
The G-protein coupled receptor 87 (GPR87) is a recently discovered orphan GPCR which means that the search of their endogenous ligands has been a novel challenge. GPR87 has been shown to be overexpressed in squamous cell carcinomas (SCCs) or adenocarcinomas in lungs and bladder. The 3D structure of GPR87 was here modeled using two templates (2VT4 and 2ZIY) by a threading method. Functional assignment of GPR87 by SVM revealed that along with transporter activity, various novel functions were predicted. The 3D structure was further validated by comparison with structural features of the templates through Verify-3D, ProSA and ERRAT for determining correct stereochemical parameters. The resulting model was evaluated by Ramachandran plot and good 3D structure compatibility was evidenced by DOPE score. Molecular dynamics simulation and solvation of protein were studied through explicit spherical boundaries with a harmonic restraint membrane water system. A DRY-motif (Asp-Arg-Tyr sequence) was found at the end of transmembrane helix3, where GPCR binds and thus activation of signals is transduced. In a search for better inhibitors of GPR87, in silico modification of some substrate ligands was carried out to form polar interactions with Arg115 and Lys296. Thus, this study provides early insights into the structure of a major drug target for SCCs.
Keywords
GPCR; GPR87; GPR95; DRY motif; threading; molecular dynamics; squamous cell carcinomas;
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1 Altschul SF, Gish W, Miller W, et al (1990). Basic local alignment search tool. J Mol Biol, 215, 403-10.   DOI
2 Arnold K, Bordoli L, Kopp J, et al (2006). The swiss-model workspace: a web-based environment for protein structure homology modeling. Bioinformatics, 22, 195-201.   DOI   ScienceOn
3 Audet M, Bouvier M (2012). Restructuring G-protein-coupled receptor activation. Cell, 151, 14-23.   DOI   ScienceOn
4 Bokoch MP, Zou Y, Rasmussen SG, et al (2010). Ligand-specific regulation of the extracellular surface of a G-protein-coupled receptor. Nature, 463, 108-12.   DOI   ScienceOn
5 Brooks BR, Bruccoleri RE, Olafson BD, et al (1993). CHARMM: a program for macromolecular energy minimization and dynamics calculations. J Comput Chem, 4, 187-217.
6 Cai CZ, Han LY, Ji ZL, et al (2003). SVM-Prot: web-based support vector machine software for functional classification of a protein from its primary sequence. Nucleic Acids Res, 31, 3692-7.   DOI   ScienceOn
7 Chung S, Funakoshi T, Civelli O (2008). Orphan GPCR research. Brit J Pharmacol, 153, 339-46.
8 Claros MG, von Heijne G (1994). TopPred II:An improved software for membrane protein structure predictions. Comput Appl Biosci, 10, 685-6.
9 Colovos C, Yeates TO (1993). Verification of protein structures: patterns of nonbonded atomic interactions. Protein Sci, 2, 1511-9.   DOI   ScienceOn
10 Combet C, Jambon M, Deleage G, et al (2002). Geno3D: An automated protein modeling Web server. Bioinformatics, 18, 213-4.   DOI   ScienceOn
11 Costanzi S (2012). Homology modeling of class a G proteincoupled receptors. Methods Mol Biol, 857, 259-79.
12 Cserzo M, Wallin E, Simon I, et al (1994). Prediction of transmembrane alpha-helices in prokaryotic membrane proteins: Application of the Dense Alignment Surface (DAS) method. J Mol Biol, 243, 388-96.   DOI   ScienceOn
13 Das S, Rani M, Pandey K, et al (2012). Combination of paromomycin and miltefosine promotes TLR4-dependent induction of antileishmanial immune response in vitro. J Antimicrob Chemother, 67, 2373-8.   DOI   ScienceOn
14 Dereeper A, Guignon V, Blanc G, et al (2008). Phylogeny.fr: robust phylogenetic analysis for the non-specialist. Nucleic Acids Res, 36, 465-9.   DOI   ScienceOn
15 Dundas J, Ouyang Z, Tseng J, et al (2006). CASTp: computed atlas of surface topography of proteins with structural and topographical mapping of functionally annotated residues. Nucleic Acid Res, 34, 116-8.
16 Glatt S, Halbauer D, Heindl S (2008). hGPR87 contributes to viability of human tumor cells. Int J Cancer, 122, 2008-16.   DOI   ScienceOn
17 Gugger M, White R, Song S (2008). GPR87 is an over expressed G-protein coupled receptor in squamous cell carcinoma of the lung. Dis Markers, 24, 41-50.   DOI
18 Hans BO, Petrine W, Anders AJ (2007). Structure, pharmacology and therapeutic prospects of family C G-protein coupled receptors. Current Drug Targets, 8, 169-84.   DOI   ScienceOn
19 Hendlich M, Rippmann F, Barnickel G (1997). LIGSITE: automatic and efficient detection of potential small moleculebinding sites in proteins. J Mol Graph Model, 15, 359-63.   DOI   ScienceOn
20 Hirokawa T, Boon-Chieng S, Mitaku S (1998). SOSUI: classification and secondary structure prediction system for membrane proteins. Bioinformatics, 14, 378-9.   DOI   ScienceOn
21 Hofmann K, Stoffel W (1993). TMbase: a database of membrane spanning proteins segments. Biol Chem Hoppe-Seyler, 374, 166-70.
22 Holm L, Kaariainen S, Rosenstrom P, et al (2008). Searching protein structure databases with DaliLitev.3. Bioinformatics, 24, 2780-1.   DOI   ScienceOn
23 Jones DT, Taylor WR, Thornton JM (1994). A model recognition approach to the prediction of all-helical membrane protein structure and topology. Biochemistry, 33, 3038-49.   DOI   ScienceOn
24 Juretic D, Zoranic L, Zucic D (2002). Basic charge clusters and predictions of membrane protein topology. J Chem Inf Comput Sci, 42, 620-32.   DOI   ScienceOn
25 Kcrley-Haniilton JS, Pike, AM, Li N, et al (2005). A p53-do mutant transcriptional response to cisplalin in testicular germ cell tumor-derived human embyomnal carcinoma. Oncoxene, 24, 6090-100.
26 Kelley LA, Sternberg MJ (2009). Protein structure prediction on the Web: a case study using the Phyre server. Nat Protoc, 4, 363-71.   DOI   ScienceOn
27 Krogh A, Larsson B, von Heijne G, et al (2001). Predicting transmembrane protein topology with a hidden Markov model: application to complete genomes. J Mol Biol, 305, 567-80   DOI   ScienceOn
28 Kyeong MK, Marc GC (2008). Complementary roles of the DRY motif and C-terminus tail of GPCRS for G protein coupling and $\beta$-arrestin interaction. Biochem Bioph Res Comm, 366, 42-7.   DOI   ScienceOn
29 Lambert N, Leonard X, De Bolle, ED (2002). ESyPred3D: prediction of proteins 3D structures. Bioinformatics, 18, 1250-6.   DOI   ScienceOn
30 Larkin MA, Blackshields G, Brown NP, et al (2007). Clustal W and Clustal X version 2.0. Bioinformatics, 23, 2947-8.   DOI   ScienceOn
31 Laskowski RA, MacArthur MW, Moss DS, et al (1993).PROCHECK: a program to check the stereochemical qualityof protein structures. J Appl Cryst, 26, 283-91.   DOI   ScienceOn
32 Mobarec JC, Sanchez R, Filizola M (2009). Modern homology modeling of G-protein coupled receptors: which structural template to use? J Med Chem, 52, 5207-16.   DOI   ScienceOn
33 Nonaka Y, Hiramoto H, Fujita N (2005). Identification of endogenous surrogate ligands for human $P2Y_{12}$ receptors by in silico and in vitro methods. Biochem Biophys Res Commun, 337, 281-8.   DOI   ScienceOn
34 Ochiai S, Furuta D, Sugita K, et al (2013). GPR87 mediates lysophosphatidic acid-induced colony dispersal in A431 cells. Eur J Pharmacol, 715, 15-20.   DOI   ScienceOn
35 Ota T, Suzuki Y, Nishikawa T, et al (2004). Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet, 36, 40-5.   DOI   ScienceOn
36 Pandian S, Shylajanaciyar MD, Murugesan R (2011). Multiple templates-based homology modeling enhances structure quality of AT1 receptor: validation by molecular dynamics and antagonist docking. J Mol Model, 17, 1565-77.   DOI   ScienceOn
37 Rani M, Dikhit MR, Sahoo GC, et al (2011) Comparative domain modeling of human EGF-like module EMR2 and study of interaction of the fourth domain of EGF with chondroitin 4-sulphate. J Biomedical Res, 25, 100-10.   DOI   ScienceOn
38 Rasmussen SG, Choi HJ, Rosenbaum DM, et al (2007). Crystal structure of the human beta2 adrenergic G-protein-coupled receptor. Nature, 15, 383-7.
39 Robert TD, Silvio JG (2007). G-protein-coupled receptors and cancer. Nature Publishing Group, 7, 79-94.
40 Roderick EH (2006). 3D Structure and the Drug Discovery Process. RSC Publishing group, 13, 9780854043514.
41 Rost B, Yachdav G, Liu J (2004). The predict protein server. Nucleic Acids Research, 32, 321-6.   DOI   ScienceOn
42 Ryckaert JP, Ciccotti G, Berendsen HJC (1977). Numerical integration of the cartesian equations of motion of a system with constraints; molecular dynamics of n-alkanes. J Comp Phys, 23, 327-41.   DOI   ScienceOn
43 Sadiq SK, Guixa-Gonzalez R, Dainese E, et al (2013). Molecular modeling and simulation of membrane lipid-mediated effects on GPCRs. Curr Med Chem, 20, 22-38.
44 Sahoo GC, Dikhit MR, Rani M, et al (2013). Analysis of sequence, structure of GAPDH of Leishmania donovani and its interactions. J Biomol Struct Dyn, 31, 258-75.   DOI   ScienceOn
45 Shailza S, Sharma DK (2011). In silico modeling in conjunction with natural products: paving the way for rational drugdesign. Biotechnology and Molecular Biology Review, 6, 88-93.
46 Shen MY, Sali A (2006). Statistical potential for assessment and prediction of protein structures. Protein Science, 15, 2507-24.   DOI   ScienceOn
47 Shimamura T, Hiraki K, Takahashi N, et al (2008). Crystal structure of squid rhodopsin with intracellularly extended cytoplasmic region. J Biol Chem, 283, 17753-6.   DOI   ScienceOn
48 Tusnady GE, Simon I (1998). Principles governing amino acid composition of integral membrane proteins - application to topology prediction. J Mol Biol, 283, 489-506.   DOI   ScienceOn
49 Varsha G (2008). Metallo beta lactamases in Pseudomonas aeruginosa and Acinetobacter species. Expert Opin Invest Drugs, 17, 131-43.   DOI   ScienceOn
50 Venkatachalam CM, Jiang X, Oldfield T et al (2003). LigandFit: a novel method for the shape-directed rapid docking of ligands to protein active sites. J Mol Graphics, 21, 289-307.   DOI   ScienceOn
51 Warne A, Serrano-Vega MJ, Baker JG, et al (2008). Structure of the Beta1-adrenergic G Protein-Coupled Receptor. Nature, 454, 454-86.
52 Wiederstein M, Sippl MJ (2007). ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Research, 35, 407-10.
53 Wittenberger T, Schaller HC, Hellebrand S (2001). An expressed sequence tag (EST) data mining strategy succeeding in the discovery of new G-protein coupled receptors. J Mol Biol, 307, 799-813.   DOI   ScienceOn
54 Zhang Y (2008). I-TASSER server for protein 3D structure prediction. BMC Bioinformatics, 9, 40.   DOI   ScienceOn