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4gl5

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==Structure of human placental aromatase complexed with designed inhibitor HDDG029 (compound 4)==
==Structure of human placental aromatase complexed with designed inhibitor HDDG029 (compound 4)==
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<StructureSection load='4gl5' size='340' side='right' caption='[[4gl5]], [[Resolution|resolution]] 3.48&Aring;' scene=''>
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<StructureSection load='4gl5' size='340' side='right'caption='[[4gl5]], [[Resolution|resolution]] 3.48&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4gl5]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GL5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GL5 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4gl5]] is a 1 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=4GL5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GL5 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=G29:(6ALPHA,8ALPHA)-6-(BUT-2-YN-1-YLOXY)ANDROSTA-1,4-DIENE-3,17-DIONE'>G29</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.48&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4gl7|4gl7]], [[3eqm|3eqm]], [[3s79|3s79]], [[3s7s|3s7s]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=G29:(6ALPHA,8ALPHA)-6-(BUT-2-YN-1-YLOXY)ANDROSTA-1,4-DIENE-3,17-DIONE'>G29</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr>
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<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>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4gl5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gl5 OCA], [https://pdbe.org/4gl5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4gl5 RCSB], [https://www.ebi.ac.uk/pdbsum/4gl5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4gl5 ProSAT]</span></td></tr>
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<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=4gl5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gl5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4gl5 RCSB], [http://www.ebi.ac.uk/pdbsum/4gl5 PDBsum]</span></td></tr>
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</table>
</table>
== Disease ==
== Disease ==
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[[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>
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[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 ==
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[[http://www.uniprot.org/uniprot/CP19A_HUMAN CP19A_HUMAN]] Catalyzes the formation of aromatic C18 estrogens from C19 androgens.
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[https://www.uniprot.org/uniprot/CP19A_HUMAN CP19A_HUMAN] Catalyzes the formation of aromatic C18 estrogens from C19 androgens.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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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<ref>PMID:22951074</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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==See Also==
==See Also==
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*[[Cytochrome P450|Cytochrome P450]]
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*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]]
== References ==
== References ==
<references/>
<references/>
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</StructureSection>
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Unspecific monooxygenase]]
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[[Category: Large Structures]]
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[[Category: Ghosh, D]]
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[[Category: Ghosh D]]
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[[Category: Cytochrome p450 reductase]]
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[[Category: Er membrane]]
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[[Category: Estrogen synthetase]]
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[[Category: Oxidoreductase]]
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[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
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Current revision

Structure of human placental aromatase complexed with designed inhibitor HDDG029 (compound 4)

PDB ID 4gl5

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