1. Structural Biology and Molecular Biophysics
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NPAS1-ARNT and NPAS3-ARNT crystal structures implicate the bHLH-PAS family as multi-ligand binding transcription factors

  1. Dalei Wu
  2. Xiaoyu Su
  3. Nalini Potluri
  4. Youngchang Kim
  5. Fraydoon Rastinejad  Is a corresponding author
  1. Shandong University, China
  2. Sanford Burnham Prebys Medical Discovery Institute, United States
  3. Argonne National Laboratory, United States
Research Article
  • Cited 21
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Cite this article as: eLife 2016;5:e18790 doi: 10.7554/eLife.18790

Abstract

The neuronal PAS domain proteins NPAS1 and NPAS3 are members of the basic helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) family, and their genetic deficiencies are linked to a variety of human psychiatric disorders including schizophrenia, autism spectrum disorders and bipolar disease. NPAS1 and NPAS3 must each heterodimerize with the aryl hydrocarbon receptor nuclear translocator (ARNT), to form functional transcription complexes capable of DNA binding and gene regulation. Here we examined the crystal structures of multi-domain NPAS1-ARNT and NPAS3-ARNT-DNA complexes, discovering each to contain four putative ligand-binding pockets. Through expanded architectural comparisons between these complexes and HIF-1α-ARNT, HIF-2α-ARNT and CLOCK-BMAL1, we show the wider mammalian bHLH-PAS family is capable of multi-ligand-binding and presents as an ideal class of transcription factors for direct targeting by small-molecule drugs.

Article and author information

Author details

  1. Dalei Wu

    State Key Laboratory of Microbial Technology, School of Life Sciences, Shandong University, Qingdao, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Xiaoyu Su

    Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Nalini Potluri

    Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Youngchang Kim

    Structural Biology Center, Argonne National Laboratory, Argonne, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Fraydoon Rastinejad

    Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, United States
    For correspondence
    frastinejad@SBPdiscovery.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0784-9352

Funding

National Institutes of Health (NIGMS 1R01GM117013)

  • Fraydoon Rastinejad

Army Research Office (W81XWH-16-1-0322)

  • Fraydoon Rastinejad

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Cynthia Wolberger, Johns Hopkins University, United States

Publication history

  1. Received: June 14, 2016
  2. Accepted: October 25, 2016
  3. Accepted Manuscript published: October 26, 2016 (version 1)
  4. Version of Record published: November 16, 2016 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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