PDBsum entry 3cbb

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protein dna_rna metals Protein-protein interface(s) links
Transcription/DNA PDB id
Jmol PyMol
Protein chains
76 a.a. *
_ZN ×4
Waters ×157
* Residue conservation analysis
PDB id:
Name: Transcription/DNA
Title: Crystal structure of hepatocyte nuclear factor 4alpha in complex with dna: diabetes gene product
Structure: Hepatocyte nuclear factor 4-alpha, DNA binding domain. Chain: a, b. Fragment: DNA binding domain. Synonym: hnf-4-alpha. Transcription factor hnf-4. Nuclear receptor subfamily 2 group a member 1. Transcription factor 14. Engineered: yes. Hepatocyte nuclear factor 4-alpha promoter
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: hnf4a, hnf4, nr2a1, tcf14. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Synthetic: yes
2.00Å     R-factor:   0.213     R-free:   0.252
Authors: P.Lu,G.B.Rha,M.Melikishvili,B.C.Adkins,M.G.Fried,Y.I.Chi
Key ref:
P.Lu et al. (2008). Structural basis of natural promoter recognition by a unique nuclear receptor, HNF4alpha. Diabetes gene product. J Biol Chem, 283, 33685-33697. PubMed id: 18829458 DOI: 10.1074/jbc.M806213200
21-Feb-08     Release date:   07-Oct-08    
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Protein chains
Pfam   ArchSchema ?
P41235  (HNF4A_HUMAN) -  Hepatocyte nuclear factor 4-alpha
474 a.a.
76 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     nucleus   1 term 
  Biological process     regulation of transcription, DNA-dependent   1 term 
  Biochemical function     sequence-specific DNA binding transcription factor activity     3 terms  


DOI no: 10.1074/jbc.M806213200 J Biol Chem 283:33685-33697 (2008)
PubMed id: 18829458  
Structural basis of natural promoter recognition by a unique nuclear receptor, HNF4alpha. Diabetes gene product.
P.Lu, G.B.Rha, M.Melikishvili, G.Wu, B.C.Adkins, M.G.Fried, Y.I.Chi.
HNF4alpha (hepatocyte nuclear factor 4alpha) plays an essential role in the development and function of vertebrate organs, including hepatocytes and pancreatic beta-cells by regulating expression of multiple genes involved in organ development, nutrient transport, and diverse metabolic pathways. As such, HNF4alpha is a culprit gene product for a monogenic and dominantly inherited form of diabetes, known as maturity onset diabetes of the young (MODY). As a unique member of the nuclear receptor superfamily, HNF4alpha recognizes target genes containing two hexanucleotide direct repeat DNA-response elements separated by one base pair (DR1) by exclusively forming a cooperative homodimer. We describe here the 2.0 angstroms crystal structure of human HNF4alpha DNA binding domain in complex with a high affinity promoter element of another MODY gene, HNF1alpha, which reveals the molecular basis of unique target gene selection/recognition, DNA binding cooperativity, and dysfunction caused by diabetes-causing mutations. The predicted effects of MODY mutations have been tested by a set of biochemical and functional studies, which show that, in contrast to other MODY gene products, the subtle disruption of HNF4alpha molecular function can cause significant effects in afflicted MODY patients.
  Selected figure(s)  
Figure 2.
Overall structure of the HNF4α-DBD·DNA complex and schematic diagrams of the protein/DNA interactions. A and B, schematic diagrams of the protein construct sequences (A) and natural response element (B) constructs used in crystallization and biochemical studies. The amino acid and nucleotide sequence numbers are shown in parenthesis at both ends. The HNF1α promoter sequence numbers were extracted from Ref. 13. C and D, schematic diagrams of protein-DNA contacts at the upstream consensus sequence half-site (C) and at the downstream half-site (D). Sequences and interactions (key is provided within the figure) are shown together for each monomer of HNF4α. Sequence-specific protein/DNA interactions and nonspecific DNA backbone interactions are indicated by brown arrows and black arrows, respectively. Water molecules are depicted as blue circles. MODY1 mutation (Arg^125) and MODY3 mutation within the HNF4α recognition sequence are shaded in light blue.
Figure 5.
Mapping of regulatory post-translational modification sites on the HNF4α-DBD structure. Phosphorylation and methylation sites are indicated by PO^-2[3] (red) and CH[3] (purple), respectively, among which the Ser^78 residue makes a hydrogen bond with the neighboring Tyr^85 residue through their hydroxyl groups.
  The above figures are reprinted from an Open Access publication published by the ASBMB: J Biol Chem (2008, 283, 33685-33697) copyright 2008.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21054848 K.M.Chow, H.Guan, and L.B.Hersh (2010).
Aminopeptidases do not directly degrade tau protein.
  Mol Neurodegener, 5, 48.  
19846556 G.B.Rha, G.Wu, S.E.Shoelson, and Y.I.Chi (2009).
Multiple binding modes between HNF4alpha and the LXXLL motifs of PGC-1alpha lead to full activation.
  J Biol Chem, 284, 35165-35176.
PDB code: 3fs1
19805548 H.Takahashi, S.Martin-Brown, M.P.Washburn, L.Florens, J.W.Conaway, and R.C.Conaway (2009).
Proteomics reveals a physical and functional link between hepatocyte nuclear factor 4alpha and transcription factor IID.
  J Biol Chem, 284, 32405-32412.  
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