Nuclear Receptor Interdomain Communication is Mediated by the Hinge with Ligand Specificity
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Abstract
Nuclear receptors are ligand-induced transcription factors that bind directly to target genes and regulate their expression. Ligand binding initiates conformational changes that propagate to other domains, allosterically regulating their activity. The nature of this interdomain communication in nuclear receptors is poorly understood, largely owing to the difficulty of experimentally characterizing full-length structures. We have applied computational modeling approaches to describe and study the structure of the full-length farnesoid X receptor (FXR), approximated by the DNA binding domain (DBD) and ligand binding domain (LBD) connected by the flexible hinge region. Using extended molecular dynamics simulations (>10 microseconds) and enhanced sampling simulations, we provide evidence that ligands selectively induce domain rearrangement, leading to interdomain contact. We use protein-protein interaction assays to provide experimental evidence of these interactions, identifying a critical role of the hinge in mediating interdomain contact. Our results illuminate previously unknown aspects of interdomain communication in FXR and provide a framework to enable characterization of other full-length nuclear receptors.
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VMD: visual molecular dynamics
Humphrey, W., Dalke, A., & Schulten, K. (1996) · Journal of Molecular Graphics · doi:10.1016/0263-7855(96)00018-5 · Cited by 66,952 · see citing works
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Development and testing of a general amber force field
Wang, J.-M., Wolf, R., Caldwell, J., Kollman, P., & Case, D. (2004) · Journal of Computational Chemistry · doi:10.1002/jcc.20035 · Cited by 18,318 · see citing works
ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB
Maier, J., Martinez, C., Kasavajhala, K., Wickstrom, L., Hauser, K., & Simmerling, C. L. (2015) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.5b00255 · Cited by 10,971 · see citing works
PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data.
Roe, D., & Cheatham, T. (2013) · Journal of Chemical Theory and Computation · doi:10.1021/ct400341p · Cited by 6,969 · see citing works
The nuclear receptor superfamily: the second decade
Mangelsdorf, D. J., Thummel, C., Beato, M., Herrlich, P., Schütz, G., Umesono, K., Blumberg, B., Kastner, P., Mark, M., Chambon, P., et al. (1995) · Cell · doi:10.1016/0092-8674(95)90199-x · Cited by 6,964 · see citing works
Accurate prediction of protein structures and interactions using a 3-track network
Baek, M., DiMaio, F., Anishchenko, I., Dauparas, J., Ovchinnikov, S., Lee, G. R., Wang, J., Cong, Q., Kinch, L. N., Schaeffer, R. D., et al. (2021) · doi:10.1101/2021.06.14.448402 · Cited by 5,542 · see citing works
Structure and Dynamics of the TIP3P, SPC, and SPC/E Water Models at 298 K
Mark, P., & Nilsson, L. (2001) · The Journal of Physical Chemistry A · doi:10.1021/jp003020w · Cited by 4,756 · see citing works
MMPBSA.py : An Efficient Program for End-State Free Energy Calculations
Miller, B. R., McGee, T. D., Swails, J., Homeyer, N., Gohlke, H., & Roitberg, A. E. (2012) · Journal of Chemical Theory and Computation · doi:10.1021/ct300418h · Cited by 4,664 · see citing works
Comparative Protein Structure Modeling Using Modeller
Eswar, N., Webb, B., Martı́-Renom, M. A., Madhusudhan, M. S., Eramian, D., Shen, M., Pieper, U., & Šali, A. (2006) · Current Protocols in Bioinformatics · doi:10.1002/0471250953.bi0506s15 · Cited by 4,564 · see citing works
Comparative Protein Structure Modeling Using MODELLER
Webb, B., & Šali, A. (2016) · Current Protocols in Bioinformatics · doi:10.1002/cpbi.3 · Cited by 4,349 · see citing works
Salomón–Ferrer, R., Götz, A. W., Poole, D., LeGrand, S., & Walker, R. C. (2013) · Journal of Chemical Theory and Computation · doi:10.1021/ct400314y · Cited by 3,373 · see citing works
MDTraj: A Modern Open Library for the Analysis of Molecular Dynamics Trajectories
McGibbon, R. T., Beauchamp, K. A., Harrigan, M. P., Klein, C., Swails, J., Hernández, C. X., Schwantes, C. R., Wang, L., Lane, T. J., & Pande, V. S. (2015) · Biophysical Journal · doi:10.1016/j.bpj.2015.08.015 · Cited by 2,358 · see citing works
Case, D. A., Aktulga, H. M., Belfon, K. A. A., Cerutti, D. S., Cisneros, G. A., Cruzeiro, V. W. D., Forouzesh, N., Giese, T. J., Götz, A. W., Gohlke, H., et al. (2023) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.3c01153 · Cited by 2,166 · see citing works
Accelerated molecular dynamics: A promising and efficient simulation method for biomolecules
Hamelberg, D., Mongan, J., & McCammon, J. A. (2004) · The Journal of Chemical Physics · doi:10.1063/1.1755656 · Cited by 1,536 · see citing works
Structure of the intact PPAR-γ–RXR-α nuclear receptor complex on DNA
Chandra, V., Huang, P., Hamuro, Y., Raghuram, S., Wang, Y., Burris, T. P., & Rastinejad, F. (2008) · Nature · doi:10.1038/nature07413 · Cited by 808 · see citing works
Pellicciari, R., Fiorucci, S., Camaioni, E., Clerici, C., Costantino, G., Maloney, P. R., Morelli, A., Parks, D. J., & Willson, T. M. (2002) · Journal of Medicinal Chemistry · doi:10.1021/jm025529g · Cited by 743 · see citing works
Shaw, D. E., Grossman, J. P., Bank, J. A., Batson, B., Butts, J. A., Chao, J. C., Deneroff, M. M., Dror, R., Even, A., Fenton, C. H., et al. (2014) · International Conference for High Performance Computing, Networking, Storage and Analysis · doi:10.1109/sc.2014.9 · Cited by 567 · see citing works
Routine Access to Millisecond Time Scale Events with Accelerated Molecular Dynamics
Pierce, L., Salomón–Ferrer, R., de Oliveira, C. A. F., McCammon, J. A., & Walker, R. C. (2012) · Journal of Chemical Theory and Computation · doi:10.1021/ct300284c · Cited by 515 · see citing works
Claudel, T., Staels, B., & Kuipers, F. (2005) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000178994.21828.a7 · Cited by 507 · see citing works
The nuclear receptor superfamily: A structural perspective
Weikum, E. R., Liu, X., & Ortlund, E. A. (2018) · Protein Science · doi:10.1002/pro.3496 · Cited by 500 · see citing works
The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer
Sun, L., Cai, J., & Gonzalez, F. J. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-00404-2 · Cited by 443 · see citing works
Structural Basis for Bile Acid Binding and Activation of the Nuclear Receptor FXR
Mi, L.-Z., Devarakonda, S., Harp, J. M., Han, Q., Pellicciari, R., Willson, T. M., Khorasanizadeh, S., & Rastinejad, F. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00112-6 · Cited by 315 · see citing works
Claudel, T., Sturm, E., Duez, H., Pineda‐Torra, I., Sirvent, A., Kosykh, V., Fruchart, J., Dallongeville, J., Hum, D. W., Kuipers, F., et al. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0214505 · Cited by 280 · see citing works
Farnesoid X receptor (FXR): Structures and ligands
Jiang, L., Zhang, H., Xiao, D., Wei, H., & Chen, Y. (2021) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2021.04.029 · Cited by 236 · see citing works
Direct prediction of intrinsically disordered protein conformational properties from sequence
Lotthammer, J. M., Ginell, G. M., Griffith, D., Emenecker, R. J., & Holehouse, A. S. (2024) · Nature Methods · doi:10.1038/s41592-023-02159-5 · Cited by 228 · see citing works
Structure of the full human RXR/VDR nuclear receptor heterodimer complex with its DR3 target DNA
Orlov, I. M., Rochel, N., Moras, D., & Klaholz, B. P. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.445 · Cited by 219 · see citing works
The Farnesoid X Receptor Controls Gene Expression in a Ligand- and Promoter-selective Fashion
Lew, J.-L., Zhao, A., Yu, J., Huang, L., de Pedro, N., Peláez, F., Wright, S. D., & Cui, J. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m306422200 · Cited by 215 · see citing works
Understanding nuclear receptor form and function using structural biology
Rastinejad, F., Huang, P., Chandra, V., & Khorasanizadeh, S. (2013) · Journal of Molecular Endocrinology · doi:10.1530/jme-13-0173 · Cited by 207 · see citing works
Multidomain integration in the structure of the HNF-4α nuclear receptor complex
Chandra, V., Huang, P., Potluri, N., Wu, D., Kim, Y., & Rastinejad, F. (2013) · Nature · doi:10.1038/nature11966 · Cited by 206 · see citing works
Farnesoid X receptor: a master regulator of hepatic triglyceride and glucose homeostasis
Jiao, Y., Lu, Y., & Li, X.-Y. (2014) · Acta Pharmacologica Sinica · doi:10.1038/aps.2014.116 · Cited by 201 · see citing works
Tetel, M. J., Giangrande, P. H., Leonhardt, S. A., McDonnell, D. P., & Edwards, D. P. (1999) · Molecular Endocrinology · doi:10.1210/mend.13.6.0300 · Cited by 172 · see citing works
Beckstein, O., Denning, E. J., Perilla, J. R., & Woolf, T. B. (2009) · Journal of Molecular Biology · doi:10.1016/j.jmb.2009.09.009 · Cited by 162 · see citing works
Structural Insights of Transcriptionally Active, Full-Length Androgen Receptor Coactivator Complexes
Yu, X., Yi, P., Hamilton, R. A., Shen, H., Chen, M., Foulds, C. E., Mancini, M. A., Ludtke, S. J., Wang, Z., & O’Malley, B. W. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.06.031 · Cited by 154 · see citing works
Molecular tuning of farnesoid X receptor partial agonism
Merk, D., Sreeramulu, S., Kudlinzki, D., Saxena, K., Linhard, V. L., Gande, S. L., Hiller, F., Lamers, C., Nilsson, E., Aagaard, A., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-10853-2 · Cited by 111 · see citing works
Structure of the retinoid X receptor α-liver X receptor β (RXRα-LXRβ) heterodimer on DNA
Lou, X., Toresson, G., Benod, C., Suh, J. H., Philips, K. J., Webb, P., & Gustafsson, J.-A. (2014) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2778 · Cited by 105 · see citing works
Interdomain interactions in the mineralocorticoid receptor
Rogerson, F. M., & Fuller, P. J. (2003) · Molecular and Cellular Endocrinology · doi:10.1016/s0303-7207(02)00413-6 · Cited by 100 · see citing works
Nuclear receptor full-length architectures: confronting myth and illusion with high resolution
Rastinejad, F., Ollendorff, V., & Polikarpov, I. (2014) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2014.10.011 · Cited by 89 · see citing works
The quaternary architecture of RARβ–RXRα heterodimer facilitates domain–domain signal transmission
Chandra, V., Wu, D., Li, S., Potluri, N., Kim, Y., & Rastinejad, F. (2017) · Nature Communications · doi:10.1038/s41467-017-00981-y · Cited by 89 · see citing works
Allosteric communication in class A β-lactamases occurs via cooperative coupling of loop dynamics
Galdadas, I., Qu, S., Oliveira, A. S. F., Olehnovics, E., Mack, A. R., Mojica, M. F., Agarwal, P. K., Tooke, C. L., Gervasio, F. L., SPENCER, J. M., et al. (2021) · eLife · doi:10.7554/elife.66567 · Cited by 77 · see citing works
Visualizing the Architectures and Interactions of Nuclear Receptors
Khorasanizadeh, S., & Rastinejad, F. (2016) · Endocrinology · doi:10.1210/en.2016-1559 · Cited by 64 · see citing works
Retinoic acid receptor structures: the journey from single domains to full-length complex
Rastinejad, F. (2022) · Journal of Molecular Endocrinology · doi:10.1530/jme-22-0113 · Cited by 51 · see citing works
Quantitative structural assessment of graded receptor agonism
Shang, J., Brust, R., Griffin, P. R., Kamenecka, T. M., & Kojetin, D. J. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1909016116 · Cited by 45 · see citing works
Maletta, M., Orlov, I. M., Roblin, P., Beck, Y., Moras, D., Billas, I. M. L., & Klaholz, B. P. (2014) · Nature Communications · doi:10.1038/ncomms5139 · Cited by 39 · see citing works
Claudel, T., Sturm, E., Duez, H., Pineda‐Torra, I., Sirvent, A., Kosykh, V., Fruchart, J., Dallongeville, J., Hum, D. W., Kuipers, F., et al. (2002) · Journal of Clinical Investigation · doi:10.1172/jci200214505 · Cited by 34 · see citing works
Seacrist, C. D., Kuenze, G., Hoffmann, R. M., Moeller, B. E., Burke, J. E., Meiler, J., & Blind, R. D. (2020) · Structure · doi:10.1016/j.str.2020.04.020 · Cited by 32 · see citing works
Fratev, F. (2015) · Physical Chemistry, Chemical Physics - PCCP · doi:10.1039/c5cp00327j · Cited by 31 · see citing works
The protein architecture and allosteric landscape of HNF4α
Rastinejad, F. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1219092 · Cited by 26 · see citing works
Quaternary glucocorticoid receptor structure highlights allosteric interdomain communication
Postel, S., Wissler, L., Johansson, C. A., Gunnarsson, A., Gordon, E., Collins, B., Castaldo, M., Köhler, C., Öling, D., Johansson, P., et al. (2023) · Nature Structural & Molecular Biology · doi:10.1038/s41594-022-00914-4 · Cited by 25 · see citing works
Identification of FDA-approved drugs targeting the Farnesoid X Receptor
van de Wiel, S. M. W., Bijsmans, I. T. G. W., van Mil, S. V., & van de Graaf, S. V. D. (2019) · Scientific Reports · doi:10.1038/s41598-019-38668-7 · Cited by 24 · see citing works
GC, J. B., Johnson, K. A., Husby, M. L., Frick, C. T., Gerstman, B. S., Stahelin, R. V., & Chapagain, P. P. (2016) · Protein Science · doi:10.1002/pro.2969 · Cited by 22 · see citing works
Structural basis of the farnesoid X receptor/retinoid X receptor heterodimer on inverted repeat DNA
Jiang, L., Liu, X., Liang, X., Dai, S., Wei, H., Guo, M., Chen, Z., Xiao, D., & Chen, Y. (2023) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2023.05.026 · Cited by 21 · see citing works
Spatial definition of the human progesterone receptor-B transcriptional complex
Yu, X., Yi, P., Panigrahi, A. K., Lumahan, L. E. V., Lydon, J. P., Lonard, D. M., Ludtke, S. J., Wang, Z., & O’Malley, B. W. (2022) · iScience · doi:10.1016/j.isci.2022.105321 · Cited by 18 · see citing works
Allosteric modulation of the farnesoid X receptor by a small molecule
Gabler, M., Kramer, J. S., Schmidt, J., Pollinger, J. C., Weber, J., Kaiser, A., Löhr, F., Proschak, E., Schubert‐Zsilavecz, M., & Merk, D. (2018) · Scientific Reports · doi:10.1038/s41598-018-25158-5 · Cited by 17 · see citing works
Full-length nuclear receptor allosteric regulation
Choi, W. J., Haratipour, Z., & Blind, R. D. (2023) · Journal of Lipid Research · doi:10.1016/j.jlr.2023.100406 · Cited by 16 · see citing works
Jacobson, B. L., He, J. J., Lemon, D. D., & Quiocho, F. A. (1992) · Journal of Molecular Biology · doi:10.1016/0022-2836(92)90712-s · Cited by 14 · see citing works
Chen, X., Jin, S., Chen, M., Bueno, C., & Wolynes, P. G. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2216906120 · Cited by 11 · see citing works
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Kydd-Sinclair, D., Packer, G., Weymouth‐Wilson, A., & Watson, K. A. (2025) · Journal of Molecular Biology · doi:10.1016/j.jmb.2025.169383 · Cited by 11 · see citing works
Tambones, I., Sagar, A., Vaňková, P., Loginov, D. S., Carivenc, C., Rochel, N., Bourguet, W., Man, P., Bernadó, P., & le Maire, A. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf967 · Cited by 10 · see citing works
Shan, X., Li, D., Yin, H., Tao, W., Zhou, L., Gao, Y. W., Xing, C., & Zhang, C. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26031207 · Cited by 7 · see citing works
Simulations Reveal Unique Roles for the FXR Hinge in the FXR–RXR Nuclear Receptor Heterodimer
Yu, T., Biswas, A., Dube, N., & Okafor, C. D. (2024) · ACS Bio & Med Chem Au · doi:10.1021/acsbiomedchemau.4c00105 · Cited by 7 · see citing works
Self-citationImpact of Bile Acid Amidation on In Silico Farnesoid X Receptor Dynamics
Sasse, R. K., Biswas, A., & Okafor, C. D. (2025) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.5c02361 · Cited by 1 · see citing works
Self-citationUnique protein dynamics distinguish the highly homologous LXR α and β isotypes
Choudhuri, K. S. R., & Okafor, C. D. (2026) · Biophysical Journal · doi:10.1016/j.bpj.2026.02.036 · Cited by 1 · see citing works
Self-citationDNA induces non-canonical dimerization of the farnesoid X receptor
Khan, S. H., Yennawar, N., & Okafor, C. D. (2026) · Nucleic Acids Research · doi:10.1093/nar/gkag087
Self-citation
- Authors
- Hazarika, S., Yu, T., Biswas, A., Dube, N., Villalona, P., & Okafor, C. D.
- Affiliations
- Pennsylvania State University (US)
- Corresponding author
- Okafor, C. Denise
- Venue
- Journal of Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2024-11
- Volume
- 436
- Issue
- 22
- Pages
- 168805
- ISSN
- 0022-2836 (ISSN-L)
- PMC
- PMC10888817
- OpenAlex
- W4402829284
- Cited by
- 7
- References
- 59
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 1
- FWCI
- 0.91
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Journal of Molecular Biology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- Funders
- National Science Foundation (2144679, CAREER)
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM116961)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- nuclear receptors, farnesoid X receptor, inter-domain communication, hinge region, ligand binding, allosteric regulation, domain rearrangement, DNA-binding domain, ligand-binding domain, protein-protein interaction
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