5jkv

HUMAN PLACENTAL AROMATASE CYTOCHROME P450 (CYP19A1) AT 2.75 ANGSTROM WITH BOUND POLYETHYLENE GLYCOL

spinqualitylabelsall models 5jkv, resolution 2.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5jkv 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 2.75Å Ligands: 1PE, ASD, HEM, PO4 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. Function CP19A_HUMAN Catalyzes the formation of aromatic C18 estrogens from C19 androgens. Publication Abstract from PubMed 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 enzyme activity in a time dependent manner. Besides its critical role in the redox partner coupling and electron transfer process, the proximal cavity possibly serves as the interaction site for other molecules that may have regulatory effects on AROM activity. In addition, the new data also reveal a previously unidentified water channel linking the active site to the lipid interface. The channel could be the predicted passage for water molecules involved in catalysis. Testosterone complex and non-steroidal ligands of human aromatase.,Ghosh D, Egbuta C, Lo J J Steroid Biochem Mol Biol. 2018 Feb 21. pii: S0960-0760(18)30105-5. doi:, 10.1016/j.jsbmb.2018.02.009. PMID:29476820 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Cytochrome P450 3D structures

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