8daf | pdb_00008daf
Human SF-1 LBD bound to synthetic agonist 6N-10CA and bacterial phospholipid
Structural highlights
DiseaseSTF1_HUMAN Defects in NR5A1 are a cause of 46,XY sex reversal type 3 (SRXY3) [MIM:612965. A condition characterized by male-to-female sex reversal in the presence of a normal 46,XY karyotype.[1] [2] [3] [4] Defects in NR5A1 are a cause of adrenocortical insufficiency without ovarian defect (ACIWOD) [MIM:184757. ACIWOD is characterized by severe 'slackness' muscular hypotonia. There is decreased sodium, increased potassium and elevated ACTH.[5] Defects in NR5A1 are the cause of premature ovarian failure type 7 (POF7) [MIM:612964. An ovarian disorder defined as the cessation of ovarian function under the age of 40 years. It is characterized by oligomenorrhea or amenorrhea, in the presence of elevated levels of serum gonadotropins and low estradiol.[6] Defects in NR5A1 are the cause of spermatogenic failure type 8 (SPGF8) [MIM:613957. SPGF8 is an infertility disorder characterized by spermatogenesis failure and severe oligozoospermia.[7] FunctionSTF1_HUMAN Transcriptional activator. Seems to be essential for sexual differentiation and formation of the primary steroidogenic tissues. Binds to the Ad4 site found in the promoter region of steroidogenic P450 genes such as CYP11A, CYP11B and CYP21B. Also regulates the AMH/Muellerian inhibiting substance gene as well as the AHCH and STAR genes. 5'-YCAAGGYC-3' and 5'-RRAGGTCA-3' are the consensus sequences for the recognition by NR5A1. The SFPQ-NONO-NR5A1 complex binds to the CYP17 promoter and regulates basal and cAMP-dependent transcriptional avtivity. Binds phosphatidylcholine (By similarity). Binds phospholipids with a phosphatidylinositol (PI) headgroup, in particular PI(3,4)P2 and PI(3,4,5)P3. Activated by the phosphorylation of NR5A1 by HIPK3 leading to increased steroidogenic gene expression upon cAMP signaling pathway stimulation.[8] Publication Abstract from PubMedSteroidogenic factor-1 (SF-1) is a phospholipid-sensing nuclear receptor expressed in the adrenal glands, gonads, and hypothalamus which controls steroidogenesis and metabolism. There is significant therapeutic interest in SF-1 because of its oncogenic properties in adrenocortical cancer. Synthetic modulators are attractive for targeting SF-1 for clinical and laboratory purposes due to the poor pharmaceutical properties of its native phospholipid ligands. While small molecule agonists targeting SF-1 have been synthesized, no crystal structures have been reported of SF-1 in complex with synthetic compounds. This has prevented the establishment of structure-activity relationships that would enable better characterization of ligand-mediated activation and improvement of current chemical scaffolds. Here, we compare the effects of small molecules in SF-1 and its close homolog, liver receptor homolog-1 (LRH-1) and identify several molecules that specifically activate LRH-1. We also report the first crystal structure of SF-1 in complex with a synthetic agonist that displays low nanomolar affinity and potency for SF-1. We use this structure to explore the mechanistic basis for small molecule agonism of SF-1, especially compared to LRH-1, and uncover unique signaling pathways that drive LRH-1 specificity. Molecular dynamics simulations reveal differences in protein dynamics at the pocket mouth, as well as ligand-mediated allosteric communication from this region to the coactivator binding interface. Our studies therefore shed important insight into the allostery driving SF-1 activity and show potential for modulation of LRH-1 over SF-1. Comparison of Activity, Structure, and Dynamics of SF-1 and LRH-1 Complexed with Small Molecule Modulators.,Cato ML, D'Agostino EH, Spurlin RM, Flynn AR, Cornelison JL, Johnson AM, Fujita RA, Abraham SM, Jui NT, Ortlund EA J Biol Chem. 2023 Jun 14:104921. doi: 10.1016/j.jbc.2023.104921. PMID:37328104[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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