2V23

Structure of cytochrome c peroxidase mutant N184R Y36A

Summary for 2V23

• Entry DOI: 10.2210/pdb2v23/pdb
• Related: 1A2F 1A2G 1AA4 1AC4 1AC8 1AEB 1AED 1AEE 1AEF 1AEG 1AEH 1AEJ 1AEK 1AEM 1AEN 1AEO 1AEQ 1AES 1AET 1AEU 1AEV 1BEJ 1BEK 1BEM 1BEP 1BEQ 1BES 1BJ9 1BVA 1CCA 1CCB 1CCC 1CCE 1CCG 1CCI 1CCJ 1CCK 1CCL 1CCP 1CMP 1CMQ 1CMT 1CMU 1CPD 1CPE 1CPF 1CPG 1CYF 1DCC 1DJ1 1DJ5 1DS4 1DSE 1DSG 1DSO 1DSP 1EBE 1JCI 1JDR 1KOK 1KRJ 1KXM 1KXN 1MK8 1MKQ 1MKR 1ML2 1RYC 1S6V 1SDQ 1SOG 1STQ 1U74 1U75 1Z53 1ZBY 1ZBZ 2B0Z 2B10 2B11 2B12 2BCN 2CCP 2CEP 2CYP 2GB8 2PCB 2PCC 3CCP 3CCX 4CCP 4CCX 5CCP 6CCP 7CCP
• Descriptor: CYTOCHROME C PEROXIDASE, PROTOPORPHYRIN IX CONTAINING FE (3 entities in total)
• Functional Keywords: cytochrome c peroxidase, transit peptide, organic radical, hydrogen peroxide, inh, ccp, iron, heme, isoniazid, peroxidase, mitochondrion, metal-binding, oxidoreductase
• Biological source: SACCHAROMYCES CEREVISIAE (BAKER'S YEAST)
• Total number of polymer chains: 1
• Total formula weight: 34398.11

Authors

Metcalfe, C.L.,Macdonald, I.K.,Brown, K.A.,Raven, E.L.,Moody, P.C.E. (deposition date: 2007-05-31, release date: 2007-12-04, Last modification date: 2023-12-13)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.8 Å)