4gl7: Difference between revisions

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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4gl7]] 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=4GL7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GL7 FirstGlance]. <br>
<table><tr><td colspan='2'>[[4gl7]] 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=4GL7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GL7 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0XJ:(6ALPHA,8ALPHA)-6-(PENT-2-YN-1-YLOXY)ANDROSTA-1,4-DIENE-3,17-DIONE'>0XJ</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</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]] 3.9&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0XJ:(6ALPHA,8ALPHA)-6-(PENT-2-YN-1-YLOXY)ANDROSTA-1,4-DIENE-3,17-DIONE'>0XJ</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></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=4gl7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gl7 OCA], [https://pdbe.org/4gl7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4gl7 RCSB], [https://www.ebi.ac.uk/pdbsum/4gl7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4gl7 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=4gl7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gl7 OCA], [https://pdbe.org/4gl7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4gl7 RCSB], [https://www.ebi.ac.uk/pdbsum/4gl7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4gl7 ProSAT]</span></td></tr>
</table>
</table>
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== Function ==
== Function ==
[https://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;">
== 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>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4gl7" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==

Latest revision as of 14:32, 1 March 2024

Structure of human placental aromatase complexed with designed inhibitor HDDG046 (compound 5)Structure of human placental aromatase complexed with designed inhibitor HDDG046 (compound 5)

Structural highlights

4gl7 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.9Å
Ligands:,
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.

See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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

4gl7, resolution 3.90Å

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OCA
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