4FDH

Structure of human aldosterone synthase, CYP11B2, in complex with fadrozole

4FDH の概要

• エントリーDOI: 10.2210/pdb4fdh/pdb
• 関連するPDBエントリー: 4DVQ
• 分子名称: Cytochrome P450 11B2, mitochondrial, PROTOPORPHYRIN IX CONTAINING FE, 4-[(5R)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl]benzonitrile, ... (4 entities in total)
• 機能のキーワード: cytochrome p450, cyp11b2, aldosterone synthase, monooxygenase, heme protein, mineralocorticoid, inhibitor, mitochondria, membrane, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Mitochondrion membrane: P19099
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 677871.12

構造登録者

Strushkevich, N.,Shen, L.,Tempel, W.,Arrowsmith, C.,Edwards, A.,Usanov, S.A.,Park, H.-W. (登録日: 2012-05-28, 公開日: 2013-01-30, 最終更新日: 2024-02-28)

主引用文献

Strushkevich, N.,Gilep, A.A.,Shen, L.,Arrowsmith, C.H.,Edwards, A.M.,Usanov, S.A.,Park, H.W.
Structural insights into aldosterone synthase substrate specificity and targeted inhibition.
Mol.Endocrinol., 27:315-324, 2013

PubMed Abstract: Aldosterone is a major mineralocorticoid hormone that plays a key role in the regulation of electrolyte balance and blood pressure. Excess aldosterone levels can arise from dysregulation of the renin-angiotensin-aldosterone system and are implicated in the pathogenesis of hypertension and heart failure. Aldosterone synthase (cytochrome P450 11B2, CYP11B2) is the sole enzyme responsible for the production of aldosterone in humans. Blocking of aldosterone synthesis by mediating aldosterone synthase activity is thus a recently emerging pharmacological therapy for hypertension, yet a lack of structural information has limited this approach. Here, we present the crystal structures of human aldosterone synthase in complex with a substrate deoxycorticosterone and an inhibitor fadrozole. The structures reveal a hydrophobic cavity with specific features associated with corticosteroid recognition. The substrate binding mode, along with biochemical data, explains the high 11β-hydroxylase activity of aldosterone synthase toward both gluco- and mineralocorticoid formation. The low processivity of aldosterone synthase with a high extent of intermediates release might be one of the mechanisms of controlled aldosterone production from deoxycorticosterone. Although the active site pocket is lined by identical residues between CYP11B isoforms, most of the divergent residues that confer additional 18-oxidase activity of aldosterone synthase are located in the I-helix (vicinity of the O(2) activation path) and loops around the H-helix (affecting an egress channel closure required for retaining intermediates in the active site). This intrinsic flexibility is also reflected in isoform-selective inhibitor binding. Fadrozole binds to aldosterone synthase in the R-configuration, using part of the active site cavity pointing toward the egress channel. The structural organization of aldosterone synthase provides critical insights into the molecular mechanism of catalysis and enables rational design of more specific antihypertensive agents.

PubMed: 23322723
DOI: 10.1210/me.2012-1287

実験手法

X-RAY DIFFRACTION (2.71 Å)