Dynamical Binding Modes Determine Agonistic and Antagonistic Ligand Effects in the Prostate-Specific G-Protein Coupled Receptor (PSGR)

Scientific Reports

Volumn 7, Issue 1, 2017, Pages

  Wolf, Steffen ^a,b   Jovancevic, Nikolina ^a   Gelis, Lian ^a   Pietsch, Sebastian ^a   Hatt, Hanns ^a   Gerwert, Klaus ^a,b  

^a RUHR UNIVERSITY BOCHUM   (Germany)

^b Shanghai Jiao Tong University Affiliated Sixth People s Hospital   (China)

Author keywords

[No Author keywords available]

Indexed keywords

G PROTEIN COUPLED RECEPTOR;

ANIMAL; CHEMISTRY; HUMAN; HYDROGEN BOND; MALE; METABOLISM; OLFACTORY RECEPTOR; PROSTATE;

ANIMALS; HUMANS; HYDROGEN BONDING; MALE; PROSTATE; RECEPTORS, G-PROTEIN-COUPLED; RECEPTORS, ODORANT;

EID: 85034833340     PISSN: None     EISSN: 20452322     Source Type: Journal    
DOI: 10.1038/s41598-017-16001-4     Document Type: Article

References (84)

1. Buck, L. & Axel, R. A novel multigene family may encode odorant receptors: A molecular basis for odor recognition. Cell 65, 175-187 (1991).
2. Neuhaus, E. M. et al. Activation of an Olfactory Receptor Inhibits Proliferation of Prostate Cancer Cells. J. Biol. Chem. 284, 16218-16225 (2009).
3. Flegel, C., Manteniotis, S., Osthold, S., Hatt, H. & Gisselmann, G. Expression Profile of Ectopic Olfactory Receptors Determined by Deep Sequencing. Plos One 8, e55368 (2013).
4. Braun, T., Voland, P., Kunz, L., Prinz, C. & Gratzl, M. Enterochromaffin Cells of the Human Gut: Sensors for Spices and Odorants. Gastroenterology 132, 1890-1901 (2007).
5. Spehr, M. et al. Identification of a testicular odorant receptor mediating human sperm chemotaxis. Science 299, 2054-2058 (2003).
6. Zhao, W. et al. Decreased level of olfactory receptors in blood cells following traumatic brain injury and potential association with tauopathy. J. Alzheimers Dis. 34, 417-429 (2013).
7. Busse, D. et al. A Synthetic Sandalwood Odorant Induces Wound-Healing Processes in Human Keratinocytes via the Olfactory Receptor OR2AT4. J. Invest. Dermatol. 134, 2823-2832 (2014).
8. Gelis, L. et al. Functional Characterization of the Odorant Receptor 51E2 in Human Melanocytes. J. Biol. Chem. jbc. M116. 734517, https://doi. org/10. 1074/jbc. M116. 734517 (2016).
9. Weng, J. S. et al. PSGR2, a novel G-protein coupled receptor, is overexpressed in human prostate cancer. Int. J. Cancer 118, 1471-1480 (2006).
10. Wang, J. H. et al. The prostate-specific G-protein coupled receptors PSGR and PSGR2 are prostate cancer biomarkers that are complementary to alpha-methylacyl-CoA racemase. Prostate 66, 847-857 (2006).
11. Fuessel, S. et al. Transcript quantification of Dresden G protein-coupled receptor (D-GPCR) in primary prostate cancer tissue pairs. Cancer Lett. 236, 95-104 (2006).
12. Cui, T. et al. Olfactory Receptor 51E1 is a Potential Novel Tissue Biomarker for the Diagnosis of Small Intestine Neuroendocrine Tumors. Pancreas 42, 373-373 (2013).
13. Giandomenico, V. et al. Olfactory receptor 51E1 as a novel target for diagnosis in somatostatin receptor-negative lung carcinoids. J. Mol. Endocrinol. 51, 277-286 (2013).
14. Maßberg, D. et al. Monoterpene (?)-citronellal affects hepatocarcinoma cell signaling via an olfactory receptor. Arch. Biochem. Biophys. 566, 100-109 (2015).
15. Manteniotis, S. et al. Functional characterization of the ectopically expressed olfactory receptor 2AT4 in human myelogenous leukemia. Cell Death Discov. 2, 15070 (2016).
16. Gelis, L., Jovancevic, N., Bechara, F., Neuhaus, E. M. & Hatt, H. Functional expression of olfactory receptors in human primary melanoma and melanoma metastasis. Exp. Dermatol. 26, 569-576 (2017).
17. Xu, L. L. et al. Quantitative expression profile of PSGR in prostate cancer. Prostate Cancer P. D. 9, 56-61 (2006).
18. Spehr, J. et al. G Protein-coupled Receptor Signaling via Src Kinase Induces Endogenous Human Transient Receptor Potential Vanilloid Type 6 (TRPV6) Channel Activation. J. Biol. Chem. 286, 13184-13192 (2011).
19. Wiese, H. et al. Quantitative phosphoproteomics reveals the protein tyrosine kinase Pyk2 as a central effector of olfactory receptor signaling in prostate cancer cells. Biochim. Biophys. Acta 1854, 632-640 (2015).
20. Schatton, T. & Frank, M. H. Review Article: Cancer stem cells and human malignant melanoma. Pigm. Cell Melanoma Res. 21, 39-55 (2007).
21. Center, M. M. et al. International variation in prostate cancer incidence and mortality rates. Eur. urol. 61, 1079-1092 (2012).
22. Wolf, S. & Grünewald, S. Sequence, Structure and Ligand Binding Evolution of Rhodopsin-Like G Protein-Coupled Receptors: A Crystal Structure-Based Phylogenetic Analysis. Plos One 10, e0123533 (2015).
23. Firestein, S. How the olfactory system makes sense of scents. Nature 413, 211-218 (2001).
24. Firestein, S., Araneda, R. C. & Kini, A. D. The molecular receptive range of an odorant receptor. Nat Neurosci 3, 1248-1255 (2000).
25. Oka, Y., Omura, M., Kataoka, H. & Touhara, K. Olfactory receptor antagonism between odorants. EMBO J. 23, 120-126 (2004).
26. Sanz, G., Schlegel, C., Pernollet, J.-C. & Briand, L. Comparison of odorant specificity of two human olfactory receptors from different phylogenetic classes and evidence for antagonism. Chem. Senses 30, 69-80 (2005).
27. Shirokova, E. et al. Identification of Specific Ligands for Orphan Olfactory Receptors: G protein-dependent agonism and antagonism of odorants. J. Biol. Chem. 280, 11807-11815 (2005).
28. Jacquier, V., Pick, H. & Vogel, H. Characterization of an extended receptive ligand repertoire of the human olfactory receptor OR17-40 comprising structurally related compounds. J. Neurochem. 97, 537-544 (2006).
29. Bavan, S., Sherman, B., Luetje, C. W. & Abaffy, T. Discovery of Novel Ligands for Mouse Olfactory Receptor MOR42-3 Using an In Silico Screening Approach and In Vitro Validation. Plos One 9, e92064 (2017).
30. Katritch, V., Cherezov, V. & Stevens, R. C. Diversity and modularity of G protein-coupled receptor structures. Trends Pharmacol Sci 33, 17-27 (2012).
31. Shepherd, G. M. Discrimination of molecular signals by the olfactory receptor neuron. Neuron 13, 771-790 (1994).
32. Kraft, P., Bajgrowicz, J. A., Denis, C. & Fráter, G. Odds and Trends: Recent Developments in the Chemistry of Odorants. Angew. Chem. Int. Ed. 39, 2980-3010 (2000).
33. Doszczak, L. et al. Prediction of Perception: Probing the hOR17-4 Olfactory Receptor Model with Silicon Analogues of Bourgeonal and Lilial. Angew. Chem. Int. Ed. 46, 3367-3371 (2007).
34. Sanz, G. et al. Relationships Between Molecular Structure and Perceived Odor Quality of Ligands for a Human Olfactory Receptor. Chem. Senses 33, 639-653 (2008).
35. Wolf, S., Gelis, L., Dörrich, S., Hatt, H. & Kraft, P. Evidence for a shape-based recognition of odorants in vivo in the human nose from an analysis of the molecular mechanism of lily-of-the-valley odorants detection in the Lilial and Bourgeonal family using the C/Si/ Ge/Sn switch strategy. Plos One 12, e0182147 (2017).
36. Turin, L. A spectroscopic mechanism for primary olfactory reception. Chem. Senses 21, 773-791 (1996).
37. Brookes, J., Horsfield, A. & Stoneham, A. The Swipe Card Model of Odorant Recognition. Sensors 12, 15709-15749 (2012).
38. Gelis, L., Wolf, S., Hatt, H., Neuhaus, E. M. & Gerwert, K. Prediction of a ligand-binding niche within a human olfactory receptor by combining site-directed mutagenesis with dynamic homology modeling. Angew. Chem. Int. Ed. Engl. 51, 1274-1278 (2012).
39. Topin, J. et al. Discrimination between Olfactory Receptor Agonists and Non-agonists. Chem. Eur. J. 20, 10227-10230 (2014).
40. Baud, O. et al. Exchanging ligand-binding specificity between a pair of mouse olfactory receptor paralogs reveals odorant recognition principles. Sci Rep 5, 14948 (2015).
41. Schneider, M., Wolf, S., Schlitter, J. & Gerwert, K. The structure of active opsin as a basis for identification of GPCR agonists by dynamic homology modelling and virtual screening assays. FEBS Lett. 585, 3587-3592 (2011).
42. Wolf, S., Böckmann, M., Höweler, U., Schlitter, J. & Gerwert, K. Simulations of a G protein-coupled receptor homology model predict dynamic features and a ligand binding site. FEBS Lett. 582, 3335-3342 (2008).
43. Trott, O. & Olson, A. J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 31, 455-461 (2010).
44. Deng, Z., Chuaqui, C. & Singh, J. Structural Interaction Fingerprint (SIFt): A Novel Method for Analyzing Three-Dimensional Protein?Ligand Binding Interactions. J. Med. Chem. 47, 337-344 (2004).
45. Kooistra, A. J., Leurs, R., de Esch, I. J. P. & de Graaf, C. Structure-Based Prediction of G-Protein-Coupled Receptor Ligand Function: A ?-Adrenoceptor Case Study. J. chem. inf. Model. 55, 1045-1061 (2015).
46. Okada, T. et al. The Retinal Conformation and its Environment in Rhodopsin in Light of a New 2. 2 ? Crystal Structure. J. Mol. Biol. 342, 571-583 (2004).
47. Park, J. H. et al. Opsin, a structural model for olfactory receptors? Angew. Chem. Int. Ed. Engl. 52, 11021-11024 (2013).
48. Kenakin, T. Efficacy at G-protein-coupled receptors. Nat. Rev. Drug Disc. 1, 103-110 (2002).
49. Kufareva, I., Rueda, M., Katritch, V., Stevens, R. C. & Abagyan, R. Status of GPCR Modeling and Docking as Reflected by Community-wide GPCR Dock 2010 Assessment. Structure 19, 1108-1126 (2011).
50. Abaffy, T., Malhotra, A. & Luetje, C. W. The molecular basis for ligand specificity in a mouse olfactory receptor: a network of functionally important residues. J. Biol. Chem. 282, 1216-1224 (2007).
51. Launay, G. et al. Automatic modeling of mammalian olfactory receptors and docking of odorants. Protein Eng. Des. Sel., 25, 377-386 (2012).
52. Li, Y. et al. Aldehyde recognition and discrimination by mammalian odorant receptors via functional group-specific hydration chemistry. ACS Chem. Biol. 9, 2563-2571 (2014).
53. Man, O. Prediction of the odorant binding site of olfactory receptor proteins by human-mouse comparisons. Protein Sci. 13, 240-254 (2004).
54. Sekharan, S. et al. QM/MM Model of the Mouse Olfactory Receptor MOR244-3 Validated by Site-Directed Mutagenesis Experiments. Biophys. J. 107, L5-L8 (2014).
55. Ballesteros, J. & Weinstein, H. Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors. In Methods in Neurosciences (eds Sealfon, S. & Conn, P.) 25, 366-428 (1995).
56. Yu, Y. et al. Responsiveness of G protein-coupled odorant receptors is partially attributed to the activation mechanism. Proc. Natl. Acad. Sci. USA 112, 14966-14971 (2015).
57. de March, C. A. et al. Conserved Residues Control Activation of Mammalian G Protein-Coupled Odorant Receptors. J. Am. Chem. Soc. 137, 8611-8616 (2015).
58. Sanz, G. et al. Structurally related odorant ligands of the olfactory receptor OR51E2 differentially promote metastasis emergence and tumor growth. Oncotarget, 8, 4330-4341 (2017).
59. Shi, L. beta 2 Adrenergic Receptor Activation. Modulation of the proline kink in transmembrane 6 by a rotamer toggle switch. J. Biol. Chem. 277, 40989-40996 (2002).
60. Pilpel, Y. & Lancet, D. The variable and conserved interfaces of modeled olfactory receptor proteins. Protein Sci. 8, 969-977 (1999).
61. Tehan, B. G., Bortolato, A., Blaney, F. E., Weir, M. P. & Mason, J. S. Unifying family A GPCR theories of activation. Pharmacol. Therapeut. 143, 51-60 (2014).
62. Kim, T. H. et al. The Role of Ligands on the Equilibria Between Functional States of a G Protein-Coupled Receptor. J. Am. Chem. Soc. 135, 9465-9474 (2013).
63. Lamichhane, R. et al. Single-molecule view of basal activity and activation mechanisms of the G protein-coupled receptor ?2AR. Proc. Natl. Acad. Sci. USA 112, 14254-14259 (2015).
64. Piechnick, R. et al. Effect of channel mutations on the uptake and release of the retinal ligand in opsin. Proc. Natl. Acad. Sci. USA 109, 5247-5252 (2012).
65. Makino, C. L., Riley, C. K., Looney, J., Crouch, R. K. & Okada, T. Binding of More Than One Retinoid to Visual Opsins. Biophys. J. 99, 2366-2373 (2010).
66. Kobilka, B. K. Structural insights into adrenergic receptor function and pharmacology. Trends Pharmacol Sci 32, 213-218 (2011).
67. Congreve, M., Oswald, C. & Marshall, F. H. Applying Structure-Based Drug Design Approaches to Allosteric Modulators of GPCRs. Trends Pharmacol Sci. 38, 837-847 (2017).
68. Plotto, A., Barnes, K. W. & Goodner, K. L. Specific Anosmia Observed for b-Ionone, but not for a-Ionone: Significance for FlavorResearch. J. Food Sci. 71, S401-S406 (2006).
69. Wang, J., Luthey-Schulten, Z. A. & Suslick, K. S. Is the olfactory receptor a metalloprotein? Proc. Natl. Acad. Sci. USA 100, 3035-3039 (2003).
70. The UniProt Consortium. Activities at the Universal Protein Resource (UniProt). Nucleic Acids Res 42, D191-D198 (2013).
71. Schuttelkopf, A. W. & van Aalten, D. M. PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr. D 60, 1355-1363 (2004).
72. Frisch, M. J. et al. Gaussian 09. Gaussian Inc (2009).
73. Olsson, M. H., Søndergaard, C. R., Rostkowski, M. & Jensen, J. H. PROPKA3: consistent treatment of internal and surface residues in empirical p K a predictions. J. Chem. Theory Comput. 7, 525-537 (2011).
74. Hess, B., Kutzner, C., Van Der Spoel, D. & Lindahl, E. GROMACS 4: Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation. J. Chem. Theory Comput. 4, 435-447 (2008).
75. Berger, O., Edholm, O. & Jähnig, F. Molecular dynamics simulations of a fluid bilayer of dipalmitoylphosphatidylcholine at full hydration, constant pressure, and constant temperature. Biophys. J. 72, 2002-2013 (1997).
76. Schmidt, T. H. & Kandt, C. LAMBADA and InflateGRO2: efficient membrane alignment and insertion of membrane proteins for molecular dynamics simulations. J. chem. inf. Model. 52, 2657-2669 (2012).
77. Rosenbaum, D. M. et al. GPCR Engineering Yields High-Resolution Structural Insights into 2-Adrenergic Receptor Function. Science 318, 1266-1273 (2007).
78. Höweler, U. MAXIMOBY 8. 1 and MOBY 3. 0 (2007).
79. Spiliotopoulos, D., Spitaleri, A. & Musco, G. Exploring PHD Fingers and H3K4me0 Interactions with Molecular Dynamics Simulations and Binding Free Energy Calculations: AIRE-PHD1, a Comparative Study. Plos One 7, e46902.
80. Paissoni, C., Spiliotopoulos, D., Musco, G. & Spitaleri, A. GMXPBSA 2. 1: A GROMACS tool to perform MM/PBSA and computational alanine scanning. Comput. Phys. Commun. 186, 105-107 (2015).
81. Zhuang, H. & Matsunami, H. Evaluating cell-surface expression and measuring activation of mammalian odorant receptors in heterologous cells. Nat Protoc 3, 1402-1413 (2008).
82. Mainland, J. D. et al. The missense of smell: functional variability in the human odorant receptor repertoire. Nat Neurosci 17, 114-120 (2013).
83. Zhuang, H. & Matsunami, H. Synergism of Accessory Factors in Functional Expression of Mammalian Odorant Receptors. J. Biol. Chem. 282, 15284-15293 (2007).
84. Li, Y. R. & Matsunami, H. Activation State of the M3 Muscarinic Acetylcholine Receptor Modulates Mammalian Odorant Receptor Signaling. Sci. Signal. 4, ra1-ra1 (2011).