4gl5
From Proteopedia
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| - | + | ==Structure of human placental aromatase complexed with designed inhibitor HDDG029 (compound 4)== | |
| - | + | <StructureSection load='4gl5' size='340' side='right' caption='[[4gl5]], [[Resolution|resolution]] 3.48Å' scene=''> | |
| - | + | == Structural highlights == | |
| + | <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> | ||
| + | </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> | ||
| + | <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> | ||
| + | <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='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> | ||
| + | </table> | ||
| + | == 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> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/CP19A_HUMAN CP19A_HUMAN]] Catalyzes the formation of aromatic C18 estrogens from C19 androgens. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == 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<ref>PMID:22951074</ref> | |
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| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
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==See Also== | ==See Also== | ||
*[[Cytochrome P450|Cytochrome P450]] | *[[Cytochrome P450|Cytochrome P450]] | ||
| - | + | == References == | |
| - | == | + | <references/> |
| - | <references | + | __TOC__ |
| + | </StructureSection> | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Unspecific monooxygenase]] | [[Category: Unspecific monooxygenase]] | ||
| - | [[Category: Ghosh, D | + | [[Category: Ghosh, D]] |
[[Category: Cytochrome p450 reductase]] | [[Category: Cytochrome p450 reductase]] | ||
[[Category: Er membrane]] | [[Category: Er membrane]] | ||
Revision as of 10:49, 21 December 2014
Structure of human placental aromatase complexed with designed inhibitor HDDG029 (compound 4)
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