7M8I

Human CYP11B2 and human adrenodoxin in complex with fadrozole

7M8I の概要

• エントリーDOI: 10.2210/pdb7m8i/pdb
• 分子名称: Adrenodoxin, Cytochrome P450 11B2, mitochondrial fusion enzyme, FE2/S2 (INORGANIC) CLUSTER, PROTOPORPHYRIN IX CONTAINING FE, ... (5 entities in total)
• 機能のキーワード: aldosterone synthase, cyp11b2, electron transfer, oxidoreductase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 211027.20

構造登録者

Scott, E.E.,Brixius-Anderko, S. (登録日: 2021-03-29, 公開日: 2021-05-26, 最終更新日: 2023-10-18)

主引用文献

Brixius-Anderko, S.,Scott, E.E.
Structural and functional insights into aldosterone synthase interaction with its redox partner protein adrenodoxin.
J.Biol.Chem., 296:100794-100794, 2021

PubMed Abstract: Aldosterone is the major mineralocorticoid in the human body controlling blood pressure and salt homeostasis. Overproduction of aldosterone leads to primary aldosteronism, which is the most common form of secondary hypertension with limited treatment options. Production of aldosterone by cytochrome P450 11B2 (CYP11B2, aldosterone synthase) requires two reduction events with the electrons delivered by the iron/sulfur protein adrenodoxin. Very limited information is available about the structural and functional basis of adrenodoxin/CYP11B2 interaction, which impedes the development of new treatment options for primary aldosteronism. A systematic study was carried out to determine if adrenodoxin interaction with CYP11B2 might also have an allosteric component in addition to electron transfer. Indeed, local increases in adrenodoxin concentration promote binding of the substrate 11-deoxycorticosterone and the inhibitor osilodrostat (LCI699) in the active site-over 17 Å away-as well as enhance the inhibitory effect of this latter drug. The CYP11B2 structure in complex with adrenodoxin identified specific residues at the protein-protein interface interacting via five salt bridges and four hydrogen bonds. Comparisons with cholesterol-metabolizing CYP11A1 and cortisol-producing CYP11B1, which also bind adrenodoxin, revealed substantial structural differences in these regions. The structural and functional differences between different P450 interactions with adrenodoxin may provide valuable clues for an orthogonal treatment approach for primary aldosteronism by specifically targeting the interaction between CYP11B2 and adrenodoxin.

PubMed: 34015331
DOI: 10.1016/j.jbc.2021.100794

実験手法

X-RAY DIFFRACTION (2.94 Å)