When Two Become One: Conformational Changes in FXR/RXR Heterodimers Bound to Steroidal Antagonists
Jazyk angličtina Země Německo Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
36398403
DOI
10.1002/cmdc.202200556
Knihovny.cz E-zdroje
- Klíčová slova
- bile acids, farnesoid X receptor, molecular dynamics simulations, nuclear receptors,
- MeSH
- DNA vazebné proteiny * chemie MeSH
- kyselina chenodeoxycholová farmakologie MeSH
- ligandy MeSH
- receptory cytoplazmatické a nukleární MeSH
- transkripční faktory * metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- DNA vazebné proteiny * MeSH
- kyselina chenodeoxycholová MeSH
- ligandy MeSH
- receptory cytoplazmatické a nukleární MeSH
- transkripční faktory * MeSH
Farnesoid X receptor (FXR) is a nuclear receptor with an essential role in regulating bile acid synthesis and cholesterol homeostasis. FXR activation by agonists is explained by an αAF-2-trapping mechanism; however, antagonism mechanisms are diverse. We discuss microsecond molecular dynamics (MD) simulations investigating our recently reported FXR antagonists 2a and 2 h. We study the antagonist-induced conformational changes in the FXR ligand-binding domain, when compared to the synthetic (GW4064) or steroidal (chenodeoxycholic acid, CDCA) FXR agonists in the FXR monomer or FXR/RXR heterodimer r, and in the presence and absence of the coactivator. Our MD data suggest ligand-specific influence on conformations of different FXR-LBD regions, including the α5/α6 region, αAF-2, and α9-11. Changes in the heterodimerization interface induced by antagonists seem to be associated with αAF-2 destabilization, which prevents both co-activator and co-repressor recruitment. Our results provide new insights into the conformational behaviour of FXR, suggesting that FXR antagonism/agonism shift requires a deeper assessment than originally proposed by crystal structures.
Faculty of Sciences Charles University Prague Albertov 6 Prague 2 12843 Czechia
PamGene International B 5 Wolvenhoek 10 5211HH 's Hertogenbosch Netherlands
School of Pharmacy Faculty of Health Sciences University of Eastern Finland Kuopio 70211 Finland
Zobrazit více v PubMed
S. Fiorucci, E. Distrutti, A. Carino, A. Zampella, M. Biagioli, Prog. Lipid Res. 2021, 82, 101094.
V. Massafra, R. Pellicciari, A. Gioiello, S. W. C. van Mil, Pharmacol. Ther. 2018, 191, 162-177.
C. Y. Han, Int. J. Mol. Sci. 2018, 19, 2069.
T. R. Ahmad, R. A. Haeusler, Nat. Rev. Endocrinol. 2019, 15, 701-712.
K. V. Kowdley, V. Luketic, R. Chapman, G. M. Hirschfield, R. Poupon, C. Schramm, C. Vincent, C. Rust, A. Parés, A. Mason, H.-U. Marschall, D. Shapiro, L. Adorini, C. Sciacca, T. Beecher-Jones, O. Böhm, R. Pencek, D. Jones, Obeticholic Acid PBC Monotherapy Study Group, Hepatology 2018, 67, 1890-1902.
L. Jiang, H. Zhang, D. Xiao, H. Wei, Y. Chen, Comput. Struct. Biotechnol. J. 2021, 19, 2148-2159.
S. De Marino, C. Festa, V. Sepe, A. Zampella, in Bile Acids and Their Receptors (Eds.: S. Fiorucci, E. Distrutti), Springer International Publishing, Cham, 2019,137-165.
Y. Anami, N. Shimizu, T. Ekimoto, D. Egawa, T. Itoh, M. Ikeguchi, K. Yamamoto, J. Med. Chem. 2016, 59, 7888-7900.
D. G. Teotico, M. L. Frazier, F. Ding, N. V. Dokholyan, B. R. S. Temple, M. R. Redinbo, PLoS Comput. Biol. 2008, 4, e1000111.
B. D. Darimont, R. L. Wagner, J. W. Apriletti, M. R. Stallcup, P. J. Kushner, J. D. Baxter, R. J. Fletterick, K. R. Yamamoto, Genes Dev. 1998, 12, 3343-3356.
B. M. Forman, E. Goode, J. Chen, A. E. Oro, D. J. Bradley, T. Perlmann, D. J. Noonan, L. T. Burka, T. McMorris, W. W. Lamph, R. M. Evans, C. Weinberger, Cell 1995, 81, 687-693.
E. G. Schuetz, S. Strom, K. Yasuda, V. Lecureur, M. Assem, C. Brimer, J. Lamba, R. B. Kim, V. Ramachandran, B. J. Komoroski, R. Venkataramanan, H. Cai, C. J. Sinal, F. J. Gonzalez, J. D. Schuetz, J. Biol. Chem. 2001, 276, 39411-39418.
D. Merk, S. Sreeramulu, D. Kudlinzki, K. Saxena, V. Linhard, S. L. Gande, F. Hiller, C. Lamers, E. Nilsson, A. Aagaard, L. Wissler, N. Dekker, K. Bamberg, M. Schubert-Zsilavecz, H. Schwalbe, Nat. Commun. 2019, 10, 2915.
W. Kilu, D. Merk, D. Steinhilber, E. Proschak, J. Heering, J. Biol. Chem. 2021, 297, 100814.
J. Heering, N. Jores, W. Kilu, E. Schallmayer, E. Peelen, A. Muehler, H. Kohlhof, D. Vitt, V. Linhard, S. L. Gande, A. Chaikuad, S. Sreeramulu, H. Schwalbe, D. Merk, ACS Chem. Biol. 2022, 17, 3159-3168.
R. T. Gampe, V. G. Montana, M. H. Lambert, G. B. Wisely, M. V. Milburn, H. E. Xu, Genes Dev. 2000, 14, 2229-2241.
T. S. Hughes, M. J. Chalmers, S. Novick, D. S. Kuruvilla, M. R. Chang, T. M. Kamenecka, M. Rance, B. A. Johnson, T. P. Burris, P. R. Griffin, D. J. Kojetin, Structure 2012, 20, 139-150.
A. K. Shiau, D. Barstad, J. T. Radek, M. J. Meyers, K. W. Nettles, B. S. Katzenellenbogen, J. A. Katzenellenbogen, D. A. Agard, G. L. Greene, Nat. Struct. Biol. 2002, 9, 359-364.
A. K. Shiau, D. Barstad, P. M. Loria, L. Cheng, P. J. Kushner, D. A. Agard, G. L. Greene, Cell 1998, 95, 927-937.
L. Jin, X. Feng, H. Rong, Z. Pan, Y. Inaba, L. Qiu, W. Zheng, S. Lin, R. Wang, Z. Wang, S. Wang, H. Liu, S. Li, W. Xie, Y. Li, Nat. Commun. 2013, 4, 1937.
X. Xu, X. Xu, P. Liu, Z. Zhu, J. Chen, H. Fu, L. Chen, L. Hu, X. Shen, J. Biol. Chem. 2015, 290, 19888-19899.
A. Rashidian, E.-K. Mustonen, T. Kronenberger, M. Schwab, O. Burk, S. A. Laufer, T. Pantsar, Comput. Struct. Biotechnol. J. 2022, 20, 3004-3018.
A. Stefela, M. Kaspar, M. Drastik, T. Kronenberger, S. Micuda, M. Dracinsky, B. Klepetarova, E. Kudova, P. Pavek, Front. Pharmacol. 2021, 12, 1980.
M. Makishima, T. T. Lu, W. Xie, G. K. Whitfield, H. Domoto, R. M. Evans, M. R. Haussler, D. J. Mangelsdorf, Science 2002, 296, 1313-1316.
N. Wang, Q. Zou, J. Xu, J. Zhang, J. Liu, J. Biol. Chem. 2018, 293, 18180-18191.
E.-K. Mustonen, T. Pantsar, A. Rashidian, J. Reiner, M. Schwab, S. Laufer, O. Burk, Cells 2022, 11, 1299.
A. I. Shulman, C. Larson, D. J. Mangelsdorf, R. Ranganathan, Cell 2004, 116, 417-429.
C. Zhang, Y. Liu, Y. Wang, X. Ge, T. Jiao, J. Yin, K. Wang, C. Li, S. Guo, X. Xie, C. Xie, F. Nan, J. Med. Chem. 2022, DOI 10.1021/acs.jmedchem.2c01394.
G. Madhavi Sastry, M. Adzhigirey, T. Day, R. Annabhimoju, W. Sherman, J. Comput.-Aided Mol. Des. 2013, 27, 221-234.
A. Akwabi-Ameyaw, J. Y. Bass, R. D. Caldwell, J. A. Caravella, L. Chen, K. L. Creech, D. N. Deaton, S. A. Jones, I. Kaldor, Y. Liu, K. P. Madauss, H. B. Marr, R. B. McFadyen, A. B. Miller, F. Navas, D. J. Parks, P. K. Spearing, D. Todd, S. P. Williams, G. B. Wisely, Bioorg. Med. Chem. Lett. 2008, 18, 4339-4343.
R. A. Friesner, J. L. Banks, R. B. Murphy, T. A. Halgren, J. J. Klicic, D. T. Mainz, M. P. Repasky, E. H. Knoll, M. Shelley, J. K. Perry, D. E. Shaw, P. Francis, P. S. Shenkin, J. Med. Chem. 2004, 47, 1739-1749.
R. O. Dror, M. Ø. Jensen, D. W. Borhani, D. E. Shaw, J. Gen. Physiol. 2010, 135, 555-62.
E. Harder, W. Damm, J. Maple, C. Wu, M. Reboul, J. Y. Xiang, L. Wang, D. Lupyan, M. K. Dahlgren, J. L. Knight, J. W. Kaus, D. S. Cerutti, G. Krilov, W. L. Jorgensen, R. Abel, R. A. Friesner, J. Chem. Theory Comput. 2016, 12, 281-296.
W. L. Jorgensen, J. Chandrasekhar, J. D. Madura, R. W. Impey, M. L. Klein, J. Chem. Phys. 1983, 79, 926-935.
T. Darden, D. York, L. Pedersen, J. Chem. Phys. 1993, 98, 10089-10092.
H. J. C. Berendsen, J. P. M. Postma, W. F. van Gunsteren, A. DiNola, J. R. Haak, J. Chem. Phys. 1984, 81, 3684-3690.
G. J. Martyna, M. L. Klein, M. Tuckerman, J. Chem. Phys. 1992, 97, 2635-2643.
G. J. Martyna, M. E. Tuckerman, D. J. Tobias, M. L. Klein, Mol. Phys. 1996, 87, 1117-1157.
J. Marelius, K. Kolmodin, I. Feierberg, J. Aqvist, J. Mol. Graphics Modell. 1998, 16, 213-225, 261.
W. Jespers, M. Esguerra, J. Åqvist, H. Gutiérrez-de-Terán, J. Cheminf. 2019, 11, 26.
F. S. Lee, A. Warshel, J. Chem. Phys. 1992, 97, 3100-3107.
G. King, A. Warshel, J. Chem. Phys. 1989, 91, 3647-3661.
J.-P. Ryckaert, G. Ciccotti, H. J. C. Berendsen, J. Comput. Phys. 1977, 23, 327-341.
J. L. Banks, H. S. Beard, Y. Cao, A. E. Cho, W. Damm, R. Farid, A. K. Felts, T. A. Halgren, D. T. Mainz, J. R. Maple, R. Murphy, D. M. Philipp, M. P. Repasky, L. Y. Zhang, B. J. Berne, R. A. Friesner, E. Gallicchio, R. M. Levy, J. Comput. Chem. 2005, 26, 1752-1780.
M. K. Scherer, B. Trendelkamp-Schroer, F. Paul, G. Pérez-Hernández, M. Hoffmann, N. Plattner, C. Wehmeyer, J.-H. Prinz, F. Noé, J. Chem. Theory Comput. 2015, 11, 5525-5542.
C. Wehmeyer, M. K. Scherer, T. Hempel, B. E. Husic, S. Olsson, F. Noé, Living J. Comput. Mol. Sci. 2019, 1, 5965-5965.
H. Wu, F. Noé, arXiv:1707.04659 [math, stat] 2019.
G. Pérez-Hernández, F. Paul, T. Giorgino, G. De Fabritiis, F. Noé, J. Chem. Phys. 2013, 139, 015102.
S. Röblitz, M. Weber, Advances in Data Analysis and Classification 2013, 7, 147-179.
P. Metzner, C. Schütte, E. Vanden-Eijnden, Multiscale Model. Simul. 2009, 7, 1192-1219.
F. Noé, C. Schütte, E. Vanden-Eijnden, L. Reich, T. R. Weikl, Proc. Natl. Acad. Sci. USA 2009, 106, 19011-19016.
J.-H. Prinz, H. Wu, M. Sarich, B. Keller, M. Senne, M. Held, J. D. Chodera, C. Schütte, F. Noé, J. Chem. Phys. 2011, 134, 174105.
J.-H. Prinz, J. D. Chodera, F. Noé, in An Introduction to Markov State Models and Their Application to Long Timescale Molecular Simulation (Eds.: G. R. Bowman, V. S. Pande, F. Noé), Springer Netherlands, Dordrecht, 2014, 45-60.
K. Beekmann, L. H. J. de Haan, L. Actis-Goretta, R. Houtman, P. J. van Bladeren, I. M. C. M. Rietjens, J. Steroid Biochem. Mol. Biol. 2015, 154, 245-253.
A. Koppen, R. Houtman, D. Pijnenburg, E. H. Jeninga, R. Ruijtenbeek, E. Kalkhoven, Mol. Cell. Proteomics 2009, 8, 2212-2226.