Journal
MOLECULAR ENDOCRINOLOGY
Volume 21, Issue 2, Pages 401-414Publisher
OXFORD UNIV PRESS INC
DOI: 10.1210/me.2006-0281
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Funding
- NCI NIH HHS [CA44735, CA33572] Funding Source: Medline
- NIEHS NIH HHS [ES08528] Funding Source: Medline
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Aromatase converts androgens to aromatic estrogens. Aromatase inhibitors have been used as first-line drugs in the treatment of hormone-dependent breast cancer. Structural basis of the aromatization reaction and drug recognition by aromatase has remained elusive because of its unknown three-dimensional structure. In this study, recombinant human aromatase was expressed and purified from Escherichia coli. Using this purified and active preparation, the three-dimensional folding of aromatase was revealed by proteomic analysis. Combined with site-directed mutagenesis, several critical residues involved in enzyme catalysis and suicide inhibition by exemestane were evaluated. Based on our results, a new clamping mechanism of substrate/ exemestane binding to the active site is proposed. These structure-function studies of aromatase would provide useful information to design more effective aromatase inhibitors for the prevention and the treatment of hormone-dependent breast cancer.
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