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Natural ligands of nuclear receptors have conserved volumes

Nature Structural Biology volume 5, pages 679–681 (1998)Cite this article

The nuclear receptor superfamily of proteins is composed of ligand-activated transcription factors that have a ligand binding domain (LBD) and a DNA binding domain (DBD)1. Recent structural studies of several different nuclear receptor LBDs with bound ligands have shown that this domain has a canonical fold consisting of 12 helices that bind a fully buried ligand in the hydrophobic core of the protein2,3,4,5. In each case the overall fold of the LBD is conserved and the ligand is bound entirely within the protein, completing the core as the protein refolds around it. Here, we show that despite the chemical diversity of the natural nuclear receptor ligands, the volumes of these ligands are highly conserved.

The sequence homology across the nuclear receptor superfamily indicates that these receptors evolved through divergent evolution5, but gives no information about the role of ligands in the evolution of these receptors. This is likely to have been important since function is conserved in evolution and these proteins are ligand-activated transcription factors. Furthermore, because the fully buried ligand plays a structural role by completing the hydrophobic core of the LBD in the active form of the receptor3, any new receptor arising from divergent evolution presumably needs a complementary ligand in order to convey a useful new function that would be selected during evolution. Considering this evolutionary argument in the context of the canonical LBD fold, one might expect the natural ligands of the nuclear receptors to be chemically similar to one another.

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Figure 1: a, The natural ligands of nuclear receptors (receptor names are in parentheses).
Figure 2: a, Proposed natural ligands of orphan nuclear receptors (orphan receptor names are in parentheses).

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Acknowledgements

A.A.B. is a National Defense Science and Engineering Graduate Fellow. T.S.S. is an Alfred P. Sloan Research Fellow. This work was supported by grants from the NIH (to T.S.S and F.E.C.). We thank D. Chapin and R. Wagner for helpful discussions.

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Authors and Affiliations

  1. Graduate Group in Biophysics, University of California , San Francisco, 94143, California, USA

    Andrew A. Bogan

  2. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, 94143, California, USA

    Fred E. Cohen & Thomas S. Scanlan

  3. Department of Pharmaceutical Chemistry, University of California, San Francisco, 94143 , California, USA

    Fred E. Cohen & Thomas S. Scanlan

  4. Department of Biochemistry and Biophysics, University of California, San Francisco, 94143 , California, USA

    Fred E. Cohen

  5. Department of Medicine, University of California, San Francisco, 94143, California, USA

    Fred E. Cohen

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  1. Andrew A. Bogan
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  2. Fred E. Cohen
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  3. Thomas S. Scanlan
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Correspondence to Andrew A. Bogan.

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Bogan, A., Cohen, F. & Scanlan, T. Natural ligands of nuclear receptors have conserved volumes. Nat Struct Mol Biol 5, 679–681 (1998). https://doi.org/10.1038/1372

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