3CBB

Crystal Structure of Hepatocyte Nuclear Factor 4alpha in complex with DNA: Diabetes Gene Product


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.213 

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This is version 1.3 of the entry. See complete history


Literature

Structural basis of natural promoter recognition by a unique nuclear receptor, HNF4alpha. Diabetes gene product.

Lu, P.Rha, G.B.Melikishvili, M.Wu, G.Adkins, B.C.Fried, M.G.Chi, Y.I.

(2008) J Biol Chem 283: 33685-33697

  • DOI: https://doi.org/10.1074/jbc.M806213200
  • Primary Citation of Related Structures:  
    3CBB

  • PubMed Abstract: 

    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.


  • Organizational Affiliation

    Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40536, USA.


Macromolecules

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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Hepatocyte Nuclear Factor 4-alpha, DNA binding domainC [auth A],
D [auth B]
78Homo sapiensMutation(s): 0 
Gene Names: HNF4AHNF4NR2A1TCF14
UniProt & NIH Common Fund Data Resources
Find proteins for P41235 (Homo sapiens)
Explore P41235 
Go to UniProtKB:  P41235
PHAROS:  P41235
GTEx:  ENSG00000101076 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP41235
Sequence Annotations
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  • Reference Sequence

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Entity ID: 1
MoleculeChains LengthOrganismImage
Hepatocyte Nuclear Factor 4-alpha promoter element DNAA [auth C]21N/A
Sequence Annotations
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  • Reference Sequence

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Entity ID: 2
MoleculeChains LengthOrganismImage
Hepatocyte Nuclear Factor 4-alpha promoter element DNAB [auth D]21N/A
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.213 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 121.628α = 90
b = 35.425β = 119.36
c = 70.985γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
CNSrefinement
PDB_EXTRACTdata extraction
HKL-2000data collection

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-10-07
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-10-25
    Changes: Refinement description
  • Version 1.3: 2024-02-21
    Changes: Data collection, Database references, Derived calculations