3P99

Sterol 14alpha-demethylase (CYP51) from Trypanosoma brucei in complex with delta7-14alpha-methylene-cyclopropyl-dihydrolanosterol

3P99 の概要

• エントリーDOI: 10.2210/pdb3p99/pdb
• 関連するPDBエントリー: 3g1q 3gw9
• 分子名称: Sterol 14-alpha-demethylase, PROTOPORPHYRIN IX CONTAINING FE, (3alpha,9beta,10alpha,13alpha)-30-cyclopropylidenelanost-7-en-3-ol, ... (4 entities in total)
• 機能のキーワード: cytochrome p450 fold/sterol 14-alpha demethylase, cyp51, oxidoreductase, monooxygenase, hemoprotein, sterol biosynthesis, cytochrome p450 reductase (cpr), endoplasmic reticulum, membrane
• 由来する生物種: Trypanosoma brucei
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 209026.65

構造登録者

Lepesheva, G.I.,Hargrove, T.Y.,Waterman, M.R.,Wawrzak, Z. (登録日: 2010-10-16, 公開日: 2011-11-30, 最終更新日: 2023-09-06)

主引用文献

Hargrove, T.Y.,Wawrzak, Z.,Liu, J.,Waterman, M.R.,Nes, W.D.,Lepesheva, G.I.
Structural complex of sterol 14alpha-demethylase (CYP51) with 14alpha-methylenecyclopropyl-delta7-24, 25-dihydrolanosterol
J.Lipid Res., 53:311-320, 2012

PubMed Abstract: Sterol 14α-demethylase (CYP51) that catalyzes the removal of the 14α-methyl group from the sterol nucleus is an essential enzyme in sterol biosynthesis, a primary target for clinical and agricultural antifungal azoles and an emerging target for antitrypanosomal chemotherapy. Here, we present the crystal structure of Trypanosoma (T) brucei CYP51 in complex with the substrate analog 14α-methylenecyclopropyl-Δ7-24,25-dihydrolanosterol (MCP). This sterol binds tightly to all protozoan CYP51s and acts as a competitive inhibitor of F105-containing (plant-like) T. brucei and Leishmania (L) infantum orthologs, but it has a much stronger, mechanism-based inhibitory effect on I105-containing (animal/fungi-like) T. cruzi CYP51. Depicting substrate orientation in the conserved CYP51 binding cavity, the complex specifies the roles of the contact amino acid residues and sheds new light on CYP51 substrate specificity. It also provides an explanation for the effect of MCP on T. cruzi CYP51. Comparison with the ligand-free and azole-bound structures supports the notion of structural rigidity as the characteristic feature of the CYP51 substrate binding cavity, confirming the enzyme as an excellent candidate for structure-directed design of new drugs, including mechanism-based substrate analog inhibitors.

PubMed: 22135275
DOI: 10.1194/jlr.M021865

実験手法

X-RAY DIFFRACTION (3 Å)