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Title: X-ray crystal structure and analysis of the Drosophila melanogaster Ultraspiracle ligand binding domain
Author: Clayton, G. M.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2002
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The nuclear receptors form a superfamily of multi-domain transcription factors that recruit transcriptional co-effector complexes required for control of gene expression. Nuclear receptors can be divided into two classes: those that bind ligand and those that have no known ligand, called orphan receptors. At present around half the mammalian nuclear receptors are orphans. In insects, with the exception of the ecdysone receptor, there are no known ligand-activated nuclear receptors and it has been suggested that the majority of insect receptors may be orphans. One of these orphan receptors, Ultraspiracle, forms heterodimers with the Ecdysone receptor. Based on sequence comparison, Ultraspiracle is the homologue of the mammalian retinoid-X-receptor (RXR). Like Ultraspiracle, RXR forms heterodimers with other nuclear receptors and has a significant role in development and homeostasis. However, unlike Ultraspiracle, RXR is regulated by a cognate ligand, 9-cis retinoic acid. Given this apparent difference between RXR and Ultraspiracle there is considerable interest in understanding how their function has changed during evolution. To understand the similarities and differences between Ultraspiracle and RXR, I have expressed, purified, crystallised and solved the structure of the Drosophila melanogaster Ultraspiracle ligand binding domain. The structure reveals that Ultraspiracle has the classic nuclear receptor, anti-parallel helical fold. Like other nuclear receptors, Ultraspiracle has a central ligand binding cavity but unexpectedly the cavity contained a lipid molecule. However, Ultraspiracle has unique structural features that set it apart from the mammalian nuclear receptors. One is an apparently inactive conformation that prevents co-effector binding. Another is that Ultraspiracle has a conserved inserted loop that is found only in the insert orders Diptera and Lepidoptera. These features suggest a structural and functional divergence between a common Ultraspiracle and RXR ancestor.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available