Protein Name

Nuclear receptor mSF-1 LBD complexed with PG(ligand)



Biological Context

Nuclear receptors have a important role in the gene transcription control. These receptors link to diabetes, dyslipidemia, or cancer cell growth, so they have attracted attention as proteins of the drug discovery targets. Most of the nuclear receptors have a DNA binding domain (DBD) with which they bind to specific sequences of DNA, and a ligand binding domain (LBD) where the signal molecules bind. The nuclear receptors are bound to inhibitory protein complexes when inactive. Ligand binding changes the conformation of the receptor to free it from the inhibitory protein complex and expose the binding site for transcriptional coactivator proteins. The Nuclear receptor superfamily is divided into various subfamilies based on sequence identity. (Table.1).

(Table.1) Classification of nuclear receptors superfamily

NR5A subfamily includes steroidogenic factor 1(SF-1) and liver receptor homolog 1(LRH-1). SF-1(NR5A1) engaged in endocrine tissue development, male sexual differentiation and controls steroid biosynthesis. LRH-1(NR5A2) is essential in early development, regulates bile acid synthesis, cholesterol transport, and ovarian function. Although physiological roles for this two receptors have emerged, ligand candidates have remained unclear. Further, notion that ligands might be dispensable for NR5A subfamily receptors was bolstered by the crystal structure of mouse LRH-1 LBD, showing an active conformation in the ligand-free hydrophobic pocket. (Fig.1). To explore how NR5A subfamily receptors are regulated, author obtained the LBD crystal structures of other members in this subfamily, including mouse SF-1(mSF-1), human SF-1(hSF-1), and human LRH-1(hLRH-1).

(Fig.1) The structure of mLRH-1 LBD

Have an active conformation with ligand-free empty hydrophobic pocket.

Structure Description


The structures shown below are three complexes of LBD and ligand(PG:phosphatidyl glycerol);mSF-1 LBD/PG, hSF-1 LBD/PG and hLRH-1 LBD/PG. (Fig.2A,B,C). All three LBDs exhibit same fold topology compared to other subfamily LBDs; with 12 α helices, two β strands. Unlike mLRH-1 above-mentioned, these three structures are bound with phospholipid(PG) in the hydrophobic pocket.

(Fig.2) Three NR5A receptors bound with ligand(PG)
(A)mSF-1 LBD
(B)hSF-1 LBD
ligand(PG) is shown in cyan、cofactor(SHP) is shown in green.

mLRH-1 have several structural differences near the hydrophobic pocket compared to these three structures. For example, three residues(Gly342,Tyr437,Lys441) of mSF-1 LBD are close to phospholipid, and provide hydrogen bonds to phosphate group of it. (Fig.3A). These interactions are crucial for phospholipid binding. On the other hand, at the corresponding region of mLRH-1, Glu440 forms a strong ionic interaction with the opposing helix Lys539, sealing the pocket. This interaction may be necessary for stabilizing the mLRH-1 LBD in the absence of the ligand. (Fig.3B). According to the hypothesis of author, ligand binding capability was ancestral in the SF-1/LRH-1, and was later lost or diminished in rodent LRH-1s due to a small number of amino acid replacement. How phospholipids are delivered to NR5A receptors remains unclear. However, this research revealed phospholipid is the ligand for NR5A receptors.

(Fig.3) Comparison of mSF-1 and mLRH-1 hydrophobic pocket
(A)Near by hydrophobic pocket of mSF-1 LBD
(B)Near by hydrophobic pocket of mLRH-1 LBD

Protein Data Bank (PDB)



Krylova, I.N. Sablin, E.P. Moore, J. Xu, R.X. Waitt, G.M. MacKay, J.A. Juzumiene, D. Bynum, J.M. Madauss, K. Montana, V. Lebedeva, L. Suzawa, M. Williams, J.D. Williams, S.P. Guy, R.K. Thornton, J.W. Fletterick, R.J. Willson, T.M. Ingraham, H.A.; "Structural analyses reveal phosphatidyl inositols as ligands for the NR5 orphan receptors SF-1 and LRH-1"; Cell (Cambridge,Mass.); (2005) 120:343-355 PubMed:15707893.


  • xPSSS:1YOW human SF-1 LBD/PG complex
  • xPSSS:1YOK human LRH-1 LBD/PG complex
  • xPSSS:1PK5 mouse LRH-1 LBD : without ligand
  • PDB:1YUC human LRH-1 LBD/PG complex: by other author at the same period
  • PDB:2A66 human LRH-1 DBD/DNA complex :DNA binding domain
  • PDB:1XNX mouse nuclear receptor CAR/ligand complex

author: Jun-ichi Ito

Japanese version:PDB:1YMT