Login Register Cart 0
Generic placeholder image

Current Chemical Biology

Editor-in-Chief

ISSN (Print): 2212-7968
ISSN (Online): 1872-3136

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Takeda G-protein Receptor (TGR)-5 Evolves Classical Activestate Conformational Signatures in Complex with Chromolaena Odorata-derived Flavonoid-5,7-dihydroxy-6-4-dimethoxyflavanone

Author(s): Omotuyi I. Olaposi*, Nash Oyekanmi, Metibemu D. Samuel, Ojochenemi A. Enejoh, Ukwenya O. Victor and Adelakun Niyi

Volume 13, Issue 3, 2019

Page: [212 - 222] Pages: 11

DOI: 10.2174/2212796813666190102102018

Price: $65

Abstract

Background: Takeda G-protein receptor 5 (TGR5) via glucagon-like peptide release and insulin signaling underlies antidiabetic roles of TGR5 agonists. Chromolaena Odorata- derived flavonoid-5,7-dihydroxy-6-4-dimethoxyflavanone (COF) has been identified as (TGR5) agonist. The structural basis for their interaction has not been studied.

Objective: This study aimed at providing both structural and dynamic insights into COF/TGR5 interaction.

Methods: Classical GPCR activation signatures (TMIII-TMVI ionic lock, toggle switches, internal water pathway) using classical MD simulation have been used.

Results: Y893.29, N933.33 and E1695.43 are key residues found to be involved in ligand binding; the continuous internal water pathway connects hydrophilic groups of the ligand to the TMIII-TMVI interface in COF-bound state, TMIII-TMVI ionic locks ruptures in COF-TGR5 complex but not antagonist-bound state, and ruptured ionic lock is associated with the evolution of active-state “VPVAM” (analogous to “NPxxY”) conformation. Dihedral angles (c2) calculated along the trajectory strongly suggest W2376.48 as a ligand-dependent toggle switch.

Conclusion: TGR5 evolves active state conformation from a starting intermediate state conformation when bound to COF, which further supports its underlying anti-diabetic activities.

Keywords: TGR5, Chromolaena odorata-derived flavonoid, internal water pathway, ionic lock, homology- based modeling, molecular dynamic simulation.

« Previous Next »
Graphical Abstract

[1]
Onyeji CO, Igbinoba SI, Olayiwola G. Therapeutic potentials and cytochrome P450-mediated interactions involving herbal products indicated for diabetes mellitus. Drug Metab Lett 2017; 11(2): 74-85.
[PMID: 29165101]
[2]
Oboh G, Adebayo AA, Ademosun AO. Erection-stimulating, anti-diabetic and antioxidant properties of Hunteria umbellata and Cylicodiscus gabunensis water extractable phytochemicals. J Complement Integr Med 2017; 15(1)
[http://dx.doi.org/10.1515/jcim-2016-0164] [PMID: 28749782]
[3]
Onkaramurthy M, Veerapur VP, Thippeswamy BS, Reddy TN, Rayappa H, Badami S. Anti-diabetic and anti-cataract effects of Chromolaena odorata Linn., in streptozotocin-induced diabetic rats. J Ethnopharmacol 2013; 145(1): 363-72.
[http://dx.doi.org/10.1016/j.jep.2012.11.023] [PMID: 23183085]
[4]
Omotuyi OI, Nash O, Inyang OK, et al. Flavonoidrich extract of Chromolaena odorata modulate circulating GLP-1 in Wistar rats: Computational evaluation of TGR5 involvement. 3 Biotech 2018; 8(2): 124.
[http://dx.doi.org/10.1007/s13205-018-1138-x] [PMID: 29450114]
[5]
Pisutthanan N, Liawruangrath B, Liawruangrath S, Bremner JB. A new flavonoid from Chromolaena odorata. Nat Prod Res 2006; 20(13): 1192-8.
[http://dx.doi.org/10.1080/14786410600899050] [PMID: 17127508]
[6]
Maruyama T, Miyamoto Y, Nakamura T, et al. Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun 2002; 298(5): 714-9.
[http://dx.doi.org/10.1016/S0006-291X(02)02550-0] [PMID: 12419312]
[7]
Brighton CA, Rievaj J, Kuhre RE, et al. Bile acids trigger GLP-1 release predominantly by accessing basolaterally located G protein-coupled bile acid receptors. Endocrinology 2015; 156(11): 3961-70.
[http://dx.doi.org/10.1210/en.2015-1321] [PMID: 26280129]
[8]
Maczewsky J, Julia K, Anne G, et al. TGR5 activation promotes stimulus-secretion coupling of pancreatic beta-cells via a PKA-dependent pathway. Diabetes 2019; 68(2): 324-36.
[http://dx.doi.org/10.2337/db18-0315] [PMID: 30409782]
[9]
Malik J, Roohi N. GLP-1, a powerful physiological incretin: an update. J Biol Regul Homeost Agents 2018; 32(5): 1171-6.
[PMID: 30334409]
[10]
Pellicciari R, Gioiello A, Macchiarulo A, et al. Discovery of 6alpha-ethyl-23(S)-methylcholic acid (S-EMCA, INT-777) as a potent and selective agonist for the TGR5 receptor, a novel target for diabesity. J Med Chem 2009; 52(24): 7958-61.
[http://dx.doi.org/10.1021/jm901390p] [PMID: 20014870]
[11]
Lo SH, Cheng KC, Li YX, Chang CH, Cheng JT, Lee KS. Development of betulinic acid as an agonist of TGR5 receptor using a new in vitro assay. Drug Des Devel Ther 2016; 10: 2669-76.
[http://dx.doi.org/10.2147/DDDT.S113197] [PMID: 27578964]
[12]
Guo C, Chen WD, Wang YD. TGR5, not only a metabolic regulator. Front Physiol 2016; 7: 646.
[http://dx.doi.org/10.3389/fphys.2016.00646] [PMID: 28082913]
[13]
Li B, Yang N, Li C, et al. INT-777, a bile acid receptor agonist, extenuates pancreatic acinar cells necrosis in a mouse model of acute pancreatitis. Biochem Biophys Res Commun 2018; 503(1): 38-44.
[http://dx.doi.org/10.1016/j.bbrc.2018.05.120] [PMID: 29859191]
[14]
Duboc H, Taché Y, Hofmann AF. The bile acid TGR5 membrane receptor: from basic research to clinical application. Dig Liver Dis 2014; 46(4): 302-12.
[http://dx.doi.org/10.1016/j.dld.2013.10.021] [PMID: 24411485]
[15]
Omotuyi OI, Nagai J, Ueda H. Lys39-lysophosphatidate carbonyl oxygen interaction locks LPA1 N-terminal cap to the orthosteric site and partners Arg124 during receptor activation. Sci Rep 2015; 5: 13343.
[http://dx.doi.org/10.1038/srep13343] [PMID: 26268898]
[16]
Tomobe K, Yamamoto E, Kholmurodov K, Yasuoka K. Water permeation through the internal water pathway in activated GPCR rhodopsin. PLoS One 2017; 12(5)e0176876
[http://dx.doi.org/10.1371/journal.pone.0176876] [PMID: 28493967]
[17]
Yuan S, Filipek S, Palczewski K, Vogel H. Activation of G-protein-coupled receptors correlates with the formation of a continuous internal water pathway. Nat Commun 2014; 5: 4733.
[http://dx.doi.org/10.1038/ncomms5733] [PMID: 25203160]
[18]
Yuan S, Wu R, Latek D, Trzaskowski B, Filipek S, Grubmuller H. Lipid receptor S1P1 activation scheme concluded from microsecond all-atom molecular dynamics simulations. PLOS Comput Biol 2013; 9(10)e1003261
[http://dx.doi.org/10.1371/journal.pcbi.1003261] [PMID: 24098103]
[19]
McAllister SD, Hurst DP, Barnett-Norris J, Lynch D, Reggio PH, Abood ME. Structural mimicry in class A G protein-coupled receptor rotamer toggle switches: The importance of the F3.36(201)/W6.48(357) interaction in cannabinoid CB1 receptor activation. J Biol Chem 2004; 279(46): 48024-37.
[http://dx.doi.org/10.1074/jbc.M406648200] [PMID: 15326174]
[20]
Li Y, Cheng KC, Niu CS, Lo SH, Cheng JT, Niu HS. Investigation of triamterene as an inhibitor of the TGR5 receptor: Identification in cells and animals. Drug Des Devel Ther 2017; 11: 1127-34.
[http://dx.doi.org/10.2147/DDDT.S131892] [PMID: 28435224]
[21]
Lovell SC, Davis IW, Arendall WB III, et al. Structure validation by Calpha geometry: Phi,psi and Cbeta deviation. Proteins 2003; 50(3): 437-50.
[http://dx.doi.org/10.1002/prot.10286] [PMID: 12557186]
[22]
Pettersen EF, Goddard TD, Huang CC, et al. UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem 2004; 25(13): 1605-12.
[http://dx.doi.org/10.1002/jcc.20084] [PMID: 15264254]
[23]
Huang J, MacKerell AD Jr. CHARMM36 all-atom additive protein force field: Validation based on comparison to NMR data. J Comput Chem 2013; 34(25): 2135-45.
[http://dx.doi.org/10.1002/jcc.23354] [PMID: 23832629]
[24]
Doerr S, Harvey MJ, Noé F, De Fabritiis G. HTMD: High-throughput molecular dynamics for molecular discovery. J Chem Theory Comput 2016; 12(4): 1845-52.
[http://dx.doi.org/10.1021/acs.jctc.6b00049] [PMID: 26949976]
[25]
Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJ. GROMACS: Fast, flexible, and free. J Comput Chem 2005; 26(16): 1701-18.
[http://dx.doi.org/10.1002/jcc.20291] [PMID: 16211538]
[26]
Harvey MJ, Giupponi G, Fabritiis GD. ACEMD: Accelerating biomolecular dynamics in the microsecond time scale. J Chem Theory Comput 2009; 5(6): 1632-9.
[http://dx.doi.org/10.1021/ct9000685] [PMID: 26609855]
[27]
Stanley N, Pardo L, Fabritiis GD. The pathway of ligand entry from the membrane bilayer to a lipid G protein-coupled receptor. Sci Rep 2016; 6: 22639.
[http://dx.doi.org/10.1038/srep22639] [PMID: 26940769]
[28]
Petrache HI, Dodd SW, Brown MF. Area per lipid and acyl length distributions in fluid phosphatidylcholines determined by (2)H NMR spectroscopy. Biophys J 2000; 79(6): 3172-92.
[http://dx.doi.org/10.1016/S0006-3495(00)76551-9] [PMID: 11106622]
[29]
DeLano WL. Pymol: An open-source molecular graphics tool. CCP4 Newsletter On Protein Crystallography 2002; 40:: 82-92.
[30]
Humphrey W, Dalke A, Schulten K. VMD: visual molecular dynamics. J Mol Graph 1996; 14(1): 33-8.27-28..
[http://dx.doi.org/10.1016/0263-7855(96)00018-5] [PMID: 8744570]

Rights & Permissions Print Cite
Article Metrics
36
2
© 2024 Bentham Science Publishers | Privacy Policy