4GL7
Structure of human placental aromatase complexed with designed inhibitor HDDG046 (compound 5)
Summary for 4GL7
| Entry DOI | 10.2210/pdb4gl7/pdb |
| Related | 3EQM 3S79 3S7S 4GL5 |
| Descriptor | Cytochrome P450 19A1, PROTOPORPHYRIN IX CONTAINING FE, (6alpha,8alpha)-6-(pent-2-yn-1-yloxy)androsta-1,4-diene-3,17-dione (3 entities in total) |
| Functional Keywords | novel aromatase inhibitor, oxidoreductase, estrogen synthetase, cytochrome p450 reductase, er membrane, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor |
| Biological source | Homo sapiens (human) |
| Cellular location | Membrane; Peripheral membrane protein: P11511 |
| Total number of polymer chains | 1 |
| Total formula weight | 58937.84 |
| Authors | Ghosh, D. (deposition date: 2012-08-13, release date: 2012-09-12, Last modification date: 2024-02-28) |
| Primary citation | Ghosh, D.,Lo, J.,Morton, D.,Valette, D.,Xi, J.,Griswold, J.,Hubbell, S.,Egbuta, C.,Jiang, W.,An, J.,Davies, H.M. Novel aromatase inhibitors by structure-guided design. J.Med.Chem., 55:8464-8476, 2012 Cited by PubMed Abstract: Human cytochrome P450 aromatase catalyzes with high specificity the synthesis of estrogens from androgens. Aromatase inhibitors (AIs) such as exemestane, 6-methylideneandrosta-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 utilization of 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 IC(50) values in the nanomolar range. Antiproliferation studies in a MCF-7 breast cancer cell line demonstrate that some of these compounds have EC(50) values better than 1 nM, exceeding that for 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. PubMed: 22951074DOI: 10.1021/jm300930n PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.9 Å) |
Structure validation
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