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The structure of the ultraspiracle ligand-binding domain reveals a nuclear receptor locked in an inactive conformation.

Clayton GM, Peak-Chew SY, Evans RM, Schwabe JW
Proc Natl Acad Sci U S A 98 1549-54 (2001)
Cited: 81 times
EuropePMC logo PMID: 11171988

Abstract

Ultraspiracle (USP) is the invertebrate homologue of the mammalian retinoid X receptor (RXR). RXR plays a uniquely important role in differentiation, development, and homeostasis through its ability to serve as a heterodimeric partner to many other nuclear receptors. RXR is able to influence the activity of its partner receptors through the action of the ligand 9-cis retinoic acid. In contrast to RXR, USP has no known high-affinity ligand and is thought to be a silent component in the heterodimeric complex with partner receptors such as the ecdysone receptor. Here we report the 2.4-A crystal structure of the USP ligand-binding domain. The structure shows that a conserved sequence motif found in dipteran and lepidopteran USPs, but not in mammalian RXRs, serves to lock USP in an inactive conformation. It also shows that USP has a large hydrophobic cavity, implying that there is almost certainly a natural ligand for USP. This cavity is larger than that seen previously for most other nuclear receptors. Intriguingly, this cavity has partial occupancy by a bound lipid, which is likely to resemble the natural ligand for USP.

Reviews - 1hg4 mentioned but not cited (1)

  1. The retinoid X receptors and their ligands. Dawson MI, Xia Z. Biochim Biophys Acta 1821 21-56 (2012)

Articles - 1hg4 mentioned but not cited (4)



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  2. Nuclear receptors--a perspective from Drosophila. King-Jones K, Thummel CS. Nat Rev Genet 6 311-323 (2005)
  3. Endocrine insights into the evolution of metamorphosis in insects. Truman JW, Riddiford LM. Annu Rev Entomol 47 467-500 (2002)
  4. Arthropod nuclear receptors and their role in molting. Nakagawa Y, Henrich VC. FEBS J 276 6128-6157 (2009)
  5. Ecdysone receptors: from the Ashburner model to structural biology. Hill RJ, Billas IM, Bonneton F, Graham LD, Lawrence MC. Annu Rev Entomol 58 251-271 (2013)
  6. Ecdysteroid hormone action. Spindler KD, Hönl C, Tremmel Ch, Braun S, Ruff H, Spindler-Barth M. Cell Mol Life Sci 66 3837-3850 (2009)
  7. Digging deep into the pockets of orphan nuclear receptors: insights from structural studies. Benoit G, Malewicz M, Perlmann T. Trends Cell Biol 14 369-376 (2004)
  8. Phospholipid--driven gene regulation. Musille PM, Kohn JA, Ortlund EA. FEBS Lett 587 1238-1246 (2013)
  9. Ecdysone-controlled expression of transgenes. Graham LD. Expert Opin Biol Ther 2 525-535 (2002)
  10. Different ligands-different receptor conformations: modeling of the hER alpha LBD in complex with agonists and antagonists. Egner U, Heinrich N, Ruff M, Gangloff M, Mueller-Fahrnow A, Wurtz JM. Med Res Rev 21 523-539 (2001)
  11. Mechanisms of vitamin A metabolism and deficiency in the mammalian and fly visual system. Dewett D, Lam-Kamath K, Poupault C, Khurana H, Rister J. Dev Biol 476 68-78 (2021)
  12. Nuclear receptors: the evolution of diversity. Schwabe JW, Teichmann SA. Sci STKE 2004 pe4 (2004)
  13. Beyond the human genome: examples of nuclear receptor analysis in model organisms and potential for drug discovery. Maglich JM, Sluder AE, Willson TM, Moore JT. Am J Pharmacogenomics 3 345-353 (2003)
  14. Co-evolution analysis on endocrine research: a methodological approach. Dou T, Chen S, Ji C, Xie Y, Mao Y. Endocrine 28 187-192 (2005)

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