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| | ==Crystal structure of human nuclear receptor sf-1 (nr5a1) bound to pip2 at 2.8 a resolution== | | ==Crystal structure of human nuclear receptor sf-1 (nr5a1) bound to pip2 at 2.8 a resolution== |
| - | <StructureSection load='4qk4' size='340' side='right' caption='[[4qk4]], [[Resolution|resolution]] 2.81Å' scene=''> | + | <StructureSection load='4qk4' size='340' side='right'caption='[[4qk4]], [[Resolution|resolution]] 2.81Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4qk4]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QK4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4QK4 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4qk4]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QK4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4QK4 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PIK:(2S)-3-{[(R)-HYDROXY{[(1R,2R,3S,4R,5R,6S)-2,3,6-TRIHYDROXY-4,5-BIS(PHOSPHONOOXY)CYCLOHEXYL]OXY}PHOSPHORYL]OXY}PROPANE-1,2-DIYL+DIHEXADECANOATE'>PIK</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.81Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AD4BP, FTZF1, NR5A1, RC2003B, SF1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PIK:(2S)-3-{[(R)-HYDROXY{[(1R,2R,3S,4R,5R,6S)-2,3,6-TRIHYDROXY-4,5-BIS(PHOSPHONOOXY)CYCLOHEXYL]OXY}PHOSPHORYL]OXY}PROPANE-1,2-DIYL+DIHEXADECANOATE'>PIK</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4qk4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qk4 OCA], [http://pdbe.org/4qk4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4qk4 RCSB], [http://www.ebi.ac.uk/pdbsum/4qk4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4qk4 ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4qk4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qk4 OCA], [https://pdbe.org/4qk4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4qk4 RCSB], [https://www.ebi.ac.uk/pdbsum/4qk4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4qk4 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/STF1_HUMAN STF1_HUMAN]] Defects in NR5A1 are a cause of 46,XY sex reversal type 3 (SRXY3) [MIM:[http://omim.org/entry/612965 612965]]. A condition characterized by male-to-female sex reversal in the presence of a normal 46,XY karyotype.<ref>PMID:10369247</ref> <ref>PMID:11932325</ref> <ref>PMID:17200175</ref> <ref>PMID:17694559</ref> Defects in NR5A1 are a cause of adrenocortical insufficiency without ovarian defect (ACIWOD) [MIM:[http://omim.org/entry/184757 184757]]. ACIWOD is characterized by severe 'slackness' muscular hypotonia. There is decreased sodium, increased potassium and elevated ACTH.<ref>PMID:11038323</ref> Defects in NR5A1 are the cause of premature ovarian failure type 7 (POF7) [MIM:[http://omim.org/entry/612964 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.<ref>PMID:19246354</ref> Defects in NR5A1 are the cause of spermatogenic failure type 8 (SPGF8) [MIM:[http://omim.org/entry/613957 613957]]. SPGF8 is an infertility disorder characterized by spermatogenesis failure and severe oligozoospermia.<ref>PMID:20887963</ref> | + | [https://www.uniprot.org/uniprot/STF1_HUMAN STF1_HUMAN] Defects in NR5A1 are a cause of 46,XY sex reversal type 3 (SRXY3) [MIM:[https://omim.org/entry/612965 612965]. A condition characterized by male-to-female sex reversal in the presence of a normal 46,XY karyotype.<ref>PMID:10369247</ref> <ref>PMID:11932325</ref> <ref>PMID:17200175</ref> <ref>PMID:17694559</ref> Defects in NR5A1 are a cause of adrenocortical insufficiency without ovarian defect (ACIWOD) [MIM:[https://omim.org/entry/184757 184757]. ACIWOD is characterized by severe 'slackness' muscular hypotonia. There is decreased sodium, increased potassium and elevated ACTH.<ref>PMID:11038323</ref> Defects in NR5A1 are the cause of premature ovarian failure type 7 (POF7) [MIM:[https://omim.org/entry/612964 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.<ref>PMID:19246354</ref> Defects in NR5A1 are the cause of spermatogenic failure type 8 (SPGF8) [MIM:[https://omim.org/entry/613957 613957]. SPGF8 is an infertility disorder characterized by spermatogenesis failure and severe oligozoospermia.<ref>PMID:20887963</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/STF1_HUMAN STF1_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.<ref>PMID:17210646</ref> [[http://www.uniprot.org/uniprot/PRGC1_HUMAN PRGC1_HUMAN]] Transcriptional coactivator for steroid receptors and nuclear receptors. Greatly increases the transcriptional activity of PPARG and thyroid hormone receptor on the uncoupling protein promoter. Can regulate key mitochondrial genes that contribute to the program of adaptive thermogenesis. Plays an essential role in metabolic reprogramming in response to dietary availability through coordination of the expression of a wide array of genes involved in glucose and fatty acid metabolism.<ref>PMID:10713165</ref> <ref>PMID:20005308</ref> <ref>PMID:21376232</ref> | + | [https://www.uniprot.org/uniprot/STF1_HUMAN STF1_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.<ref>PMID:17210646</ref> |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | 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.
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| - | | + | |
| - | The signaling phospholipid PIP3 creates a new interaction surface on the nuclear receptor SF-1.,Blind RD, Sablin EP, Kuchenbecker KM, Chiu HJ, Deacon AM, Das D, Fletterick RJ, Ingraham HA Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):15054-9. doi:, 10.1073/pnas.1416740111. Epub 2014 Oct 6. PMID:25288771<ref>PMID:25288771</ref>
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| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 4qk4" style="background-color:#fffaf0;"></div>
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| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Structural genomic]] | + | [[Category: Large Structures]] |
| - | [[Category: STEMCELL, Partnership for Stem Cell Biology]]
| + | |
| - | [[Category: Jcsg]]
| + | |
| - | [[Category: Nr5a1]]
| + | |
| - | [[Category: Nuclear hormone receptor]]
| + | |
| - | [[Category: Nuclear phosphatidylinositol phosphate]]
| + | |
| - | [[Category: Nucleus]]
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| - | [[Category: Partnership for stem cell biology]]
| + | |
| - | [[Category: Pip2]]
| + | |
| - | [[Category: Pip3]]
| + | |
| - | [[Category: PSI, Protein structure initiative]]
| + | |
| - | [[Category: Psi-biology]]
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| - | [[Category: Regulatory ligand]]
| + | |
| - | [[Category: Sf-1 ligand binding domain]]
| + | |
| - | [[Category: Stemcell]]
| + | |
| - | [[Category: Transcription]]
| + | |
| - | [[Category: Transcription factor-hormone complex]]
| + | |
| - | [[Category: Transcription regulation]]
| + | |
| Structural highlights
Disease
STF1_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]
Function
STF1_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]
References
- ↑ Achermann JC, Ito M, Ito M, Hindmarsh PC, Jameson JL. A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nat Genet. 1999 Jun;22(2):125-6. PMID:10369247 doi:10.1038/9629
- ↑ Achermann JC, Ozisik G, Ito M, Orun UA, Harmanci K, Gurakan B, Jameson JL. Gonadal determination and adrenal development are regulated by the orphan nuclear receptor steroidogenic factor-1, in a dose-dependent manner. J Clin Endocrinol Metab. 2002 Apr;87(4):1829-33. PMID:11932325
- ↑ Lin L, Philibert P, Ferraz-de-Souza B, Kelberman D, Homfray T, Albanese A, Molini V, Sebire NJ, Einaudi S, Conway GS, Hughes IA, Jameson JL, Sultan C, Dattani MT, Achermann JC. Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function. J Clin Endocrinol Metab. 2007 Mar;92(3):991-9. Epub 2007 Jan 2. PMID:17200175 doi:10.1210/jc.2006-1672
- ↑ Kohler B, Lin L, Ferraz-de-Souza B, Wieacker P, Heidemann P, Schroder V, Biebermann H, Schnabel D, Gruters A, Achermann JC. Five novel mutations in steroidogenic factor 1 (SF1, NR5A1) in 46,XY patients with severe underandrogenization but without adrenal insufficiency. Hum Mutat. 2008 Jan;29(1):59-64. PMID:17694559 doi:10.1002/humu.20588
- ↑ Biason-Lauber A, Schoenle EJ. Apparently normal ovarian differentiation in a prepubertal girl with transcriptionally inactive steroidogenic factor 1 (NR5A1/SF-1) and adrenocortical insufficiency. Am J Hum Genet. 2000 Dec;67(6):1563-8. Epub 2000 Oct 18. PMID:11038323 doi:S0002-9297(07)63224-8
- ↑ Lourenco D, Brauner R, Lin L, De Perdigo A, Weryha G, Muresan M, Boudjenah R, Guerra-Junior G, Maciel-Guerra AT, Achermann JC, McElreavey K, Bashamboo A. Mutations in NR5A1 associated with ovarian insufficiency. N Engl J Med. 2009 Mar 19;360(12):1200-10. doi: 10.1056/NEJMoa0806228. Epub 2009 , Feb 25. PMID:19246354 doi:10.1056/NEJMoa0806228
- ↑ Bashamboo A, Ferraz-de-Souza B, Lourenco D, Lin L, Sebire NJ, Montjean D, Bignon-Topalovic J, Mandelbaum J, Siffroi JP, Christin-Maitre S, Radhakrishna U, Rouba H, Ravel C, Seeler J, Achermann JC, McElreavey K. Human male infertility associated with mutations in NR5A1 encoding steroidogenic factor 1. Am J Hum Genet. 2010 Oct 8;87(4):505-12. doi: 10.1016/j.ajhg.2010.09.009. PMID:20887963 doi:10.1016/j.ajhg.2010.09.009
- ↑ Lan HC, Li HJ, Lin G, Lai PY, Chung BC. Cyclic AMP stimulates SF-1-dependent CYP11A1 expression through homeodomain-interacting protein kinase 3-mediated Jun N-terminal kinase and c-Jun phosphorylation. Mol Cell Biol. 2007 Mar;27(6):2027-36. Epub 2007 Jan 8. PMID:17210646 doi:10.1128/MCB.02253-06
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