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| | ==Crystal structure of human placental aromatase complexed with breast cancer drug exemestane== | | ==Crystal structure of human placental aromatase complexed with breast cancer drug exemestane== |
| - | <StructureSection load='3s7s' size='340' side='right' caption='[[3s7s]], [[Resolution|resolution]] 3.21Å' scene=''> | + | <StructureSection load='3s7s' size='340' side='right'caption='[[3s7s]], [[Resolution|resolution]] 3.21Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3s7s]] is a 1 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=3S7S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3S7S FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3s7s]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3S7S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3S7S FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EXM:(8ALPHA,10ALPHA,13ALPHA)-6-METHYLIDENEANDROSTA-1,4-DIENE-3,17-DIONE'>EXM</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EXM:(8ALPHA,10ALPHA,13ALPHA)-6-METHYLIDENEANDROSTA-1,4-DIENE-3,17-DIONE'>EXM</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3eqm|3eqm]], [[3s79|3s79]]</td></tr> | + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3eqm|3eqm]], [[3s79|3s79]]</div></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP19A1, ARO1, CYAR, CYP19 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP19A1, ARO1, CYAR, CYP19 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Unspecific_monooxygenase Unspecific monooxygenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.14.1 1.14.14.1] </span></td></tr> | + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Unspecific_monooxygenase Unspecific monooxygenase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.14.1 1.14.14.1] </span></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=3s7s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3s7s OCA], [http://pdbe.org/3s7s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3s7s RCSB], [http://www.ebi.ac.uk/pdbsum/3s7s PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3s7s 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=3s7s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3s7s OCA], [https://pdbe.org/3s7s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3s7s RCSB], [https://www.ebi.ac.uk/pdbsum/3s7s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3s7s ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/CP19A_HUMAN CP19A_HUMAN]] Defects in CYP19A1 are a cause of aromatase excess syndrome (AEXS) [MIM:[http://omim.org/entry/139300 139300]]; also known as familial gynecomastia. AEXS is characterized by an estrogen excess due to an increased aromatase activity. Defects in CYP19A1 are the cause of aromatase deficiency (AROD) [MIM:[http://omim.org/entry/613546 613546]]. AROD is a rare disease in which fetal androgens are not converted into estrogens due to placental aromatase deficiency. Thus, pregnant women exhibit a hirsutism, which spontaneously resolves after post-partum. At birth, female babies present with pseudohermaphroditism due to virilization of extern genital organs. In adult females, manifestations include delay of puberty, breast hypoplasia and primary amenorrhoea with multicystic ovaries.<ref>PMID:8265607</ref> <ref>PMID:8530621</ref> <ref>PMID:9211678</ref> | + | [[https://www.uniprot.org/uniprot/CP19A_HUMAN CP19A_HUMAN]] Defects in CYP19A1 are a cause of aromatase excess syndrome (AEXS) [MIM:[https://omim.org/entry/139300 139300]]; also known as familial gynecomastia. AEXS is characterized by an estrogen excess due to an increased aromatase activity. Defects in CYP19A1 are the cause of aromatase deficiency (AROD) [MIM:[https://omim.org/entry/613546 613546]]. AROD is a rare disease in which fetal androgens are not converted into estrogens due to placental aromatase deficiency. Thus, pregnant women exhibit a hirsutism, which spontaneously resolves after post-partum. At birth, female babies present with pseudohermaphroditism due to virilization of extern genital organs. In adult females, manifestations include delay of puberty, breast hypoplasia and primary amenorrhoea with multicystic ovaries.<ref>PMID:8265607</ref> <ref>PMID:8530621</ref> <ref>PMID:9211678</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CP19A_HUMAN CP19A_HUMAN]] Catalyzes the formation of aromatic C18 estrogens from C19 androgens. | + | [[https://www.uniprot.org/uniprot/CP19A_HUMAN CP19A_HUMAN]] Catalyzes the formation of aromatic C18 estrogens from C19 androgens. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 3s7s" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 3s7s" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Human]] | | [[Category: Human]] |
| | + | [[Category: Large Structures]] |
| | [[Category: Unspecific monooxygenase]] | | [[Category: Unspecific monooxygenase]] |
| | [[Category: Ghosh, D]] | | [[Category: Ghosh, D]] |
| Structural highlights
3s7s is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , |
| Related: | |
| Gene: | CYP19A1, ARO1, CYAR, CYP19 (HUMAN) |
| Activity: | Unspecific monooxygenase, with EC number 1.14.14.1 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[CP19A_HUMAN] Defects in CYP19A1 are a cause of aromatase excess syndrome (AEXS) [MIM:139300]; also known as familial gynecomastia. AEXS is characterized by an estrogen excess due to an increased aromatase activity. Defects in CYP19A1 are the cause of aromatase deficiency (AROD) [MIM:613546]. AROD is a rare disease in which fetal androgens are not converted into estrogens due to placental aromatase deficiency. Thus, pregnant women exhibit a hirsutism, which spontaneously resolves after post-partum. At birth, female babies present with pseudohermaphroditism due to virilization of extern genital organs. In adult females, manifestations include delay of puberty, breast hypoplasia and primary amenorrhoea with multicystic ovaries.[1] [2] [3]
Function
[CP19A_HUMAN] Catalyzes the formation of aromatic C18 estrogens from C19 androgens.
Publication Abstract from PubMed
Human cytochrome P450 aromatase catalyzes with high specificity the synthesis of estrogens from androgens. Aromatase inhibitors (AIs) such as exemestane, 6-methylidene-androsta-1,4-diene-3,17-dione, are preeminent drugs for the treatment of estrogen-dependent breast cancer. The crystal structure of human placental aromatase has shown an androgen-specific active site. By utilizing the structural data, novel C6-substituted androsta-1,4-diene-3,17-dione inhibitors have been designed. Several of the C6-substituted 2-alkynyloxy compounds inhibit purified placental aromatase with IC50s in the nM range. Anti-proliferation studies in a MCF-7 breast cancer cell line demonstrate that some of these compounds have EC50s better than 1nM, exceeding exemestane. X-ray structures of aromatase-complexes of two potent compounds reveal that, per their design, the novel side groups protrude into the opening to the access channel unoccupied in the enzyme-substrate/exemestane complexes. The observed structure-activity relationship is borne out by the X-ray data. Structure-guided design permits utilization of the aromatase-specific interactions for the development of next generation AIs.
Novel Aromatase Inhibitors By Structure-Guided Design.,Ghosh D, Lo J, Xi J, Hubbell S, Egbuta C, Jiang W, An J, Morton D, Valette D, Griswold J, Davies HM J Med Chem. 2012 Sep 5. PMID:22951074[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ito Y, Fisher CR, Conte FA, Grumbach MM, Simpson ER. Molecular basis of aromatase deficiency in an adult female with sexual infantilism and polycystic ovaries. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11673-7. PMID:8265607
- ↑ Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K. Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab. 1995 Dec;80(12):3689-98. PMID:8530621
- ↑ Carani C, Qin K, Simoni M, Faustini-Fustini M, Serpente S, Boyd J, Korach KS, Simpson ER. Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med. 1997 Jul 10;337(2):91-5. PMID:9211678 doi:10.1056/NEJM199707103370204
- ↑ Ghosh D, Lo J, Xi J, Hubbell S, Egbuta C, Jiang W, An J, Morton D, Valette D, Griswold J, Davies HM. Novel Aromatase Inhibitors By Structure-Guided Design. J Med Chem. 2012 Sep 5. PMID:22951074 doi:http://dx.doi.org/10.1021/jm300930n
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