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Related Experiment Videos

Structural basis of VDR-DNA interactions on direct repeat response elements.

Paul L Shaffer1, Daniel T Gewirth

  • 1Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.

The EMBO Journal
|May 1, 2002
PubMed
Summary
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Structural insights into the vitamin D receptor (VDR) reveal how it binds DNA. Mutations alter VDR

Area of Science:

  • Molecular biology
  • Structural biology
  • Biochemistry

Background:

  • The vitamin D receptor (VDR) is crucial for gene regulation.
  • VDR functions by binding to specific DNA sequences as homo- or heterodimers.
  • Understanding VDR-DNA interactions is key to VDR-mediated signaling.

Purpose of the Study:

  • To elucidate the structural basis of VDR's differential binding to various DNA response elements.
  • To investigate the VDR homodimerization interface and its role in DNA binding.
  • To explore VDR's interaction with the 9-cis retinoic acid receptor (RXR).

Main Methods:

  • X-ray crystallography of VDR DNA-binding domain (DBD) complexes.
  • Analysis of VDR-DNA complexes with osteopontin (SPP), DR3, and osteocalcin (OC) response elements.

Related Experiment Videos

  • Structure-based site-directed mutagenesis of the VDR DBD.

    • Main Results:

    • Crystal structures revealed VDR DBD bound to SPP, DR3, and OC response elements.
    • Identified specific interactions explaining VDR's higher affinity for SPP and lower stability with OC.
    • Characterized the non-polar, van der Waals-stabilized homodimeric interface of VDR DBD.
    • An alpha-helix at the VDR DBD C-terminus may mediate response element discrimination, similar to thyroid hormone receptor (TR).
    • Mutations disrupted VDR homodimerization but enabled heterodimerization with RXR DBD.

    Conclusions:

    • Structural data provides chemical basis for VDR's differential DNA binding.
    • The VDR DBD C-terminal helix is implicated in response element selectivity.
    • VDR homodimerization can be modulated to promote heterodimerization with RXR.