3R9B

Crystal structure of Mycobacterium smegmatis CYP164A2 in ligand free state

3R9B の概要

• エントリーDOI: 10.2210/pdb3r9b/pdb
• 関連するPDBエントリー: 3R9C
• 分子名称: CYTOCHROME P450 164A2, PROTOPORPHYRIN IX CONTAINING FE, PHOSPHATE ION, ... (8 entities in total)
• 機能のキーワード: cytochrome p450, monooxygenase, oxidoreductase
• 由来する生物種: Mycobacterium smegmatis
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 140597.23

構造登録者

Agnew, C.R.J.,Warrilow, A.G.S.,Kelly, S.L.,Brady, R.L. (登録日: 2011-03-25, 公開日: 2012-04-04, 最終更新日: 2024-03-20)

主引用文献

Agnew, C.R.,Warrilow, A.G.,Burton, N.M.,Lamb, D.C.,Kelly, S.L.,Brady, R.L.
An enlarged, adaptable active site in CYP164 family P450 enzymes, the sole P450 in Mycobacterium leprae.
Antimicrob.Agents Chemother., 56:391-402, 2012

PubMed Abstract: CYP164 family P450 enzymes are found in only a subset of mycobacteria and include CYP164A1, which is the sole P450 found in Mycobacterium leprae, the causative agent of leprosy. This has previously led to interest in this enzyme as a potential drug target. Here we describe the first crystal structure of a CYP164 enzyme, CYP164A2 from Mycobacterium smegmatis. CYP164A2 has a distinctive, enlarged hydrophobic active site that extends above the porphyrin ring toward the access channels. Unusually, we find that CYP164A2 can simultaneously bind two econazole molecules in different regions of the enlarged active site and is accompanied by the rearrangement and ordering of the BC loop. The primary location is through a classic interaction of the azole group with the porphyrin iron. The second econazole molecule is bound to a unique site and is linked to a tetracoordinated metal ion complexed to one of the heme carboxylates and to the side chains of His 105 and His 364. All of these features are preserved in the closely homologous M. leprae CYP164A1. The computational docking of azole compounds to a homology model of CYP164A1 suggests that these compounds will form effective inhibitors and is supported by the correlation of parallel docking with experimental binding studies of CYP164A2. The binding of econazole to CYP164A2 occurs primarily through the high-spin "open" conformation of the enzyme (K(d) [dissociation constant] of 0.1 μM), with binding to the low-spin "closed" form being significantly hindered (K(d) of 338 μM). These studies support previous suggestions that azole derivatives may provide an effective strategy to improve the treatment of leprosy.

PubMed: 22037849
DOI: 10.1128/AAC.05227-11

実験手法

X-RAY DIFFRACTION (1.89 Å)