Testosterone complex and non-steroidal ligands of human aromatase

The Journal of Steroid Biochemistry and Molecular Biology
Debashis GhoshJessica Lo

Abstract

Cytochrome P450 aromatase (AROM) catalyzes the biosynthesis of estrogen from androgen. Previously crystal structures of human AROM in complex with the substrate androstenedione, and inhibitors exemestane, as well as the newly designed steroidal compounds, have been reported. Here we report the first crystal structure of testosterone complex of human placental AROM. Testosterone binds at the androgen-specific heme distal pocket. The polar and hydrophobic interactions with the surrounding residues resemble the interactions observed for other ligands. The heme proximal region comprises the intermolecular interface in AROM, and also the putative interaction surface of its redox partner cytochrome P450 reductase. Unreported previously, the proximal region is characterized by a large surface cavity, unlike most known P450's. Using five best X-ray data sets from androstenedione and testosterone complexes of AROM, we now unequivocally show the presence of an unexplained ligand electron density inside the proximal cavity. The density is interpreted as ordered five ethylene glycol units of polyethylene glycols used as a solvent for steroids and also in crystallization. Interestingly, polyethylene glycol exhibits weak inhibition of AROM e...Continue Reading

Citations

Jul 25, 2019·Expert Opinion on Drug Discovery·Angelo SpinelloAlessandra Magistrato
Jan 11, 2020·Proceedings of the National Academy of Sciences of the United States of America·Montserrat Elías-Arnanz
May 31, 2020·International Journal of Molecular Sciences·Karina Angélica Méndez-ReséndizSara Luz Morales-Lázaro
Oct 28, 2019·The Biochemical Journal·Debashis GhoshTuKiet T Lam
Nov 20, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jessica CaciollaSilvia Gobbi
Jul 23, 2020·International Journal of Biological Macromolecules·Chao ZhangGianfranco Gilardi
Jul 1, 2020·Anti-cancer Agents in Medicinal Chemistry·Pooja RatreSuresh Thareja
Aug 31, 2021·RSC Chemical Biology·Samson A SouzaHo Leung Ng

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