4QJR: Crystal structure of human nuclear receptor sf-1 (nr5a1) bound to its hormone pip3 at 2.4 a resolution

Citation:
Abstract
The signaling phosphatidylinositol lipids PI(4,5)P2 (PIP2) and PI(3,4,5)P3 (PIP3) bind nuclear receptor 5A family (NR5As), but their regulatory mechanisms remain unknown. Here, the crystal structures of human NR5A1 (steroidogenic factor-1, SF-1) ligand binding domain (LBD) bound to PIP2 and PIP3 show the lipid hydrophobic tails sequestered in the hormone pocket, as predicted. However, unlike classic nuclear receptor hormones, the phosphoinositide head groups are fully solvent-exposed and complete the LBD fold by organizing the receptor architecture at the hormone pocket entrance. The highest affinity phosphoinositide ligand PIP3 stabilizes the coactivator binding groove and increases coactivator peptide recruitment. This receptor-ligand topology defines a previously unidentified regulatory protein-lipid surface on SF-1 with the phosphoinositide head group at its nexus and poised to interact with other proteins. This surface on SF-1 coincides with the predicted binding site of the corepressor DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region on chromosome X), and importantly harbors missense mutations associated with human endocrine disorders. Our data provide the structural basis for this poorly understood cluster of human SF-1 mutations and demonstrates how signaling phosphoinositides function as regulatory ligands for NR5As.
PDB ID: 4QJRDownload
MMDB ID: 121973
PDB Deposition Date: 2014/6/4
Updated in MMDB: 2017/12
Experimental Method:
x-ray diffraction
Resolution: 2.4  Å
Source Organism:
Homo sapiens
Similar Structures:
Biological Unit for 4QJR: dimeric; determined by author and by software (PISA)
Molecular Components in 4QJR
Label Count Molecule
Proteins (2 molecules)
1
Steroidogenic Factor 1(Gene symbol: NR5A1)
Molecule annotation
1
Peroxisome Proliferator-activated Receptor Gamma Coactivator 1-alpha(Gene symbol: PPARGC1A)
Molecule annotation
Chemicals (3 molecules)
1
1
2
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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