2VCF

Structure of isoniazid (INH) bound to cytosolic soybean ascorbate peroxidase

2VCF の概要

• エントリーDOI: 10.2210/pdb2vcf/pdb
• 関連するPDBエントリー: 1OAF 1OAG 1V0H 2CL4 2GGN 2GHC 2GHD 2GHE 2GHH 2GHK
• 分子名称: ASCORBATE PEROXIDASE FROM SOYBEAN CYTOSOL, 4-(DIAZENYLCARBONYL)PYRIDINE, PROTOPORPHYRIN IX CONTAINING FE, ... (5 entities in total)
• 機能のキーワード: cytochrome c peroxidase, ccp, inh, isoniazid, peroxidase, oxidoreductase
• 由来する生物種: GLYCINE MAX (SOYBEAN)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29670.08

構造登録者

Metcalfe, C.L.,Macdonald, I.K.,Brown, K.A.,Raven, E.L.,Moody, P.C.E. (登録日: 2007-09-21, 公開日: 2007-12-04, 最終更新日: 2023-12-13)

主引用文献

Metcalfe, C.L.,Macdonald, I.K.,Murphy, E.J.,Brown, K.A.,Raven, E.L.,Moody, P.C.E.
The Tuberculosis Prodrug Isoniazid Bound to Activating Peroxidases.
J.Biol.Chem., 283:6193-, 2008

PubMed Abstract: Isoniazid (INH, isonicotinic acid hydrazine) is one of only two therapeutic agents effective in treating tuberculosis. This prodrug is activated by the heme enzyme catalase peroxidase (KatG) endogenous to Mycobacterium tuberculosis but the mechanism of activation is poorly understood, in part because the binding interaction has not been properly established. The class I peroxidases ascorbate peroxidase (APX) and cytochrome c peroxidase (CcP) have active site structures very similar to KatG and are also capable of activating isoniazid. We report here the first crystal structures of complexes of isoniazid bound to APX and CcP. These are the first structures of isoniazid bound to any activating enzymes. The structures show that isoniazid binds close to the delta-heme edge in both APX and CcP, although the precise binding orientation varies slightly in the two cases. A second binding site for INH is found in APX at the gamma-heme edge close to the established ascorbate binding site, indicating that the gamma-heme edge can also support the binding of aromatic substrates. We also show that in an active site mutant of soybean APX (W41A) INH can bind directly to the heme iron to become an inhibitor and in a different mode when the distal histidine is replaced by alanine (H42A). These structures provide the first unambiguous evidence for the location of the isoniazid binding site in the class I peroxidases and provide rationalization of isoniazid resistance in naturally occurring KatG mutant strains of M. tuberculosis.

PubMed: 18056997
DOI: 10.1074/JBC.M707412200

実験手法

X-RAY DIFFRACTION (1.8 Å)