The DOI matches its Crossref record; 28 of the 28 references it cites were found in a registry or an index.
Multidomain integration in the structure of the HNF-4α nuclear receptor complex
Open accessAbstract
The hepatocyte nuclear factor 4α (HNF-4α; also known as NR2A1) is a member of the nuclear receptor (NR) family of transcription factors, which have conserved DNA-binding domains and ligand-binding domains. HNF-4α is the most abundant DNA-binding protein in the liver, where some 40% of the actively transcribed genes have a HNF-4α response element. These regulated genes are largely involved in the hepatic gluconeogenic program and lipid metabolism. In the pancreas HNF-4α is also a master regulator, controlling an estimated 11% of islet genes. HNF-4α protein mutations are linked to maturity-onset diabetes of the young, type 1 (MODY1) and hyperinsulinaemic hypoglycaemia. Previous structural analyses of NRs, although productive in elucidating the structure of individual domains, have lagged behind in revealing the connectivity patterns of NR domains. Here we describe the 2.9 Å crystal structure of the multidomain human HNF-4α homodimer bound to its DNA response element and coactivator-derived peptides. A convergence zone connects multiple receptor domains in an asymmetric fashion, joining distinct elements from each monomer. An arginine target of PRMT1 methylation protrudes directly into this convergence zone and sustains its integrity. A serine target of protein kinase C is also responsible for maintaining domain-domain interactions. These post-translational modifications lead to changes in DNA binding by communicating through the tightly connected surfaces of the quaternary fold. We find that some MODY1 mutations, positioned on the ligand-binding domain and hinge regions of the receptor, compromise DNA binding at a distance by communicating through the interjunctional surfaces of the complex. The overall domain representation of the HNF-4α homodimer is different from that of the PPAR-γ-RXR-α heterodimer, even when both NR complexes are assembled on the same DNA element. Our findings suggest that unique quaternary folds and interdomain connections in NRs could be exploited by small-molecule allosteric modulators that affect distal functions in these polypeptides.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“This LBD-DBD domain arrangement is similar to the HNF4α dimer that was solved by X-ray crystallography (Chandra et al., 2013), which is different from the non-symmetric PPARγ-RXRα dimer (Chandra et al., 2008) or the X-shape LBD-DBD crossing arrangement in RXRα-LXRβ dimer (Lou et al., 2014).”
From Structural Insights of Transcriptionally Active, Full-Length Androgen Receptor Coactivator Complexes (2020) · cites this paper as Chandra et al., 2013
The cited source says what the claim attributes to it.
In the citing paper
“Previously published full-length nuclear hormone receptor structures (Chandra et al., 2008; Chandra et al., 2013; Lou et al., 2014; Orlov et al., 2012) also do not present any NTD information.”
From Structural Insights of Transcriptionally Active, Full-Length Androgen Receptor Coactivator Complexes (2020) · cites this paper as Chandra et al., 2013
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
The RXR heterodimers and orphan receptors
Mangelsdorf, D. J., & Evans, R. M. (1995) · Cell · doi:10.1016/0092-8674(95)90200-7 · Cited by 3,165
Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1
Yoon, J. C., Puigserver, P., Chen, G., Donovan, J., Wu, Z., Rhee, J., Adelmant, G., Stafford, J., Kahn, C. R., Granner, D. K., et al. (2001) · Nature · doi:10.1038/35093050 · Cited by 1,821
Control of Pancreas and Liver Gene Expression by HNF Transcription Factors
Odom, D. T., Zizlsperger, N., Gordon, D. B., Bell, G. W., Rinaldi, N. J., Murray, H. L., Volkert, T. L., Schreiber, J., Rolfe, A., Gifford, D. K., et al. (2004) · Science · doi:10.1126/science.1089769 · Cited by 1,348
Sladek, F. M., Zhong, W. M., Lai, E., & Darnell, J. E. (1990) · Genes & Development · doi:10.1101/gad.4.12b.2353 · Cited by 1,027
Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARγ by Cdk5
Choi, J. H., Banks, A. S., Estall, J. L., Kajimura, S., Boström, P., Laznik, D., Ruas, J. L., Chalmers, M. J., Kamenecka, T. M., Blüher, M., et al. (2010) · Nature · doi:10.1038/nature09291 · Cited by 897
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
Self-citationDNA binding site sequence directs glucocorticoid receptor structure and activity
Meijsing, S. H., Pufall, M. A., So, A. Y., Bates, D. L., Chen, L., & Yamamoto, K. R. (2009) · Science · doi:10.1126/science.1164265 · Cited by 673
Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation
Choi, J. H., Banks, A. S., Kamenecka, T. M., Busby, S. A., Chalmers, M. J., Kumar, N., Kuruvilla, D. S., Shin, Y., He, Y., Bruning, J. B., et al. (2011) · Nature · doi:10.1038/nature10383 · Cited by 541
Nielsen, R., Pedersen, T. Å., Hagenbeek, D., Moulos, P., Siersbæk, R., Megens, E., Denissov, S., Børgesen, M., Françoijs, K., Mandrup, S., et al. (2008) · Genes & Development · doi:10.1101/gad.501108 · Cited by 520
Hepatocyte nuclear factor 4 is a transcription factor that constitutively binds fatty acids
Wisely, G. B., Miller, A. B., Davis, R. G., Thornquest, A. D., Johnson, R., Spitzer, T., Sefler, A., Shearer, B., Moore, J. T., Miller, A. B., et al. (2002) · Structure · doi:10.1016/s0969-2126(02)00829-8 · Cited by 311
Flagged first, then by citations
Cited by
Sorted by citations
Items 201–208 of 208
Kanlayaprasit, S., Parnich, W., Jantheang, T., Lertpeerapan, P., Panjabud, P., Kasitipradit, K., Poolcharoen, C., Saeliw, T., Muangnoi, C., Plaingam, W., et al. (2026) · Nutrients · doi:10.3390/nu18081200
Phenotypic Spectrum of HNF4α-Associated Fanconi Renotubular Syndrome
Emma, F., Böckenhauer, D., Mallett, A. J., Raina, R., Sethi, S. K., der Cingel, G. H.-V., Bald, M., Tal, L., Pöhl, M., Courbebaisse, M., et al. (2026) · Kidney International Reports · doi:10.1016/j.ekir.2026.106616
Li, J., Zhang, J., Ren, S., Liu, Y., Wu, C., Dong, J. I. A. N. Z. E., Zhu, C. F., Chen, S., Zhang, H., Li, T. H., et al. (2026) · Acta Diabetologica · doi:10.1007/s00592-026-02731-3
The enabling power of chemical probes: examples from the nuclear hormone receptor field
Willson, T. M., & Merk, D. (2026) · Essays in Biochemistry · doi:10.1042/ebc20260016
He, L., Huang, B., Ma, H., Wang, L., Wu, Q., Zhang, J., Yu, L., & Lv, S. (2026) · Virology Journal · doi:10.1186/s12985-026-03132-2
“Meanwhile, interactions between HNF4A (pdb_00004iqr) [24] and G4 structures were predicted via the powerful online platform AlphaFold3.”
BindingDB Entry 50023754: A First-in-Class Hepatocyte Nuclear Factor 4 Agonist.
BindingDB (2026) · UC San Diego · doi:10.7270/q2vq37n5
Jiménez‐Panizo, A., Johnson, T. A., Wagh, K., Alegre‐Martí, A., Montoya-Novoa, I., Lafuente, A. L., Eckhard, U., Rodríguez‐Lumbreras, L. A., Hoang, L., Stortz, M., et al. (2025) · Zenodo (CERN European Organization for Nuclear Research) · doi:10.5281/zenodo.15659398
Metadata
- Authors
- Chandra, V., Huang, P., Potluri, N., Wu, D., Kim, Y., & Rastinejad, F.
- Affiliations
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Argonne National Laboratory (US)
- Corresponding author
- Rastinejad, Fraydoon
- Venue
- Nature
- Published
- 2013-03
- Volume
- 495
- Issue
- 7441
- Pages
- 394-398
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3606643
- OpenAlex
- W2025155497
- Cited by
- 206
- References
- 28
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 11 · 2023: 19 · 2022: 18 · 2021: 11 · 2020: 17 · 2019: 14 · 2018: 15 · 2017: 10 · 2016: 17 · 2015: 20 · 2014: 16 · 2013: 10
- FWCI
- 9.41
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Lirias (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK097475, R01DK094147)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- HNF4α, nuclear receptors, DNA response elements, coactivator peptide, homodimer, protein kinase C phosphorylation, post-translational modification, maturity-onset diabetes of the young, transcriptional regulation
- MeSH terms
- Humans, Hypoglycemia, Models, Molecular, Mutation, Protein Binding, Point Mutation, Protein Structure, Tertiary, Protein Structure, Quaternary, Hepatocyte Nuclear Factor 4
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
