Abstract：
:The orphan nuclear receptors SF-1 and LRH-1 are constitutively active, but it remains uncertain whether their activation is hormone dependent. We report the crystal structure of the LRH-1 ligand binding domain to 2.4 A resolution and find the receptor to be a monomer that adopts an active conformation with a large but empty hydrophobic pocket. Adding bulky side chains into this pocket resulted in full or greater activity suggesting that, while LRH-1 could accommodate potential ligands, these are dispensable for basal activity. Constitutive LRH-1 activity appears to be conferred by a distinct structural element consisting of an extended helix 2 that provides an additional layer to the canonical LBD fold. Mutating the conserved arginine in helix 2 reduced LRH-1 receptor activity and coregulator recruitment, consistent with the partial loss-of-function phenotype exhibited by an analogous SF-1 human mutant. These findings illustrate an alternative structural strategy for nuclear receptor stabilization in the absence of ligand binding.
journal_name
Mol Celljournal_title
Molecular cellauthors
Sablin EP,Krylova IN,Fletterick RJ,Ingraham HAdoi
10.1016/s1097-2765(03)00236-3subject
Has Abstractpub_date
2003-06-01 00:00:00pages
1575-85issue
6eissn
1097-2765issn
1097-4164pii
S1097-2765(03)00236-3journal_volume
11pub_type
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