PDBsum entry 3ae7

Oxidoreductase/oxidoreductase inhibitor

PDB id: 3ae7

Contents

Protein chains

613 a.a. *

239 a.a. *

138 a.a. *

102 a.a. *

Ligands

FAD

FES

SF4

F3S

12J

HEM

* Residue conservation analysis

PDB id:

3ae7

Name:

Oxidoreductase/oxidoreductase inhibitor

Title:

Crystal structure of porcine heart mitochondrial complex ii bound with 2-iodo-n-(3-isopropoxy-phenyl)-benzamide

Structure:

Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial. Chain: a. Synonym: flavoprotein subunit of complex ii, fp. Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial. Chain: b. Synonym: iron-sulfur subunit of complex ii, ip. Succinate dehydrogenase cytochrome b560 subunit,

Source:

Sus scrofa. Pig. Organism_taxid: 9823. Organ: heart. Tissue: muscle. Tissue: muscle

Resolution:

3.62Å R-factor: 0.259 R-free: 0.305

Authors:

S.Harada,T.Sasaki,M.Shindo,Y.Kido,D.K.Inaoka,J.Omori,A.Osanai, K.Sakamoto,J.Mao,S.Matsuoka,M.Inoue,T.Honma,A.Tanaka,K.Kita

Key ref:

D.K.Inaoka et al. (2015). Structural Insights into the Molecular Design of Flutolanil Derivatives Targeted for Fumarate Respiration of Parasite Mitochondria. Int J Mol Sci, 16, 15287-15308. PubMed id: 26198225 DOI: 10.3390/ijms160715287

Date:

04-Feb-10 Release date: 09-Feb-11

Protein chain

Q0QF01  (SDHA_PIG) -  Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial from Sus scrofa

Seq: 664 a.a.

Struc: 613 a.a.

Protein chain

Q007T0  (SDHB_PIG) -  Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial from Sus scrofa

Seq: 280 a.a.

Struc: 239 a.a.

Protein chain

D0VWV4  (C560_PIG) -  Succinate dehydrogenase cytochrome b560 subunit, mitochondrial from Sus scrofa

Seq: 169 a.a.

Struc: 138 a.a.

Protein chain

A5GZW8  (DHSD_PIG) -  Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial from Sus scrofa

Seq: 159 a.a.

Struc: 102 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class 2: Chains A, B: E.C.1.1.5.- - ?????
• Enzyme class 3: Chains A, B: E.C.1.3.5.1 - succinate dehydrogenase.

Pathway:

• Reaction: a quinone + succinate = fumarate + a quinol
• Cofactor: FAD; Iron-sulfur

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.3390/ijms160715287

Int J Mol Sci 16:15287-15308 (2015)

PubMed id: 26198225

Structural Insights into the Molecular Design of Flutolanil Derivatives Targeted for Fumarate Respiration of Parasite Mitochondria.

D.K.Inaoka, T.Shiba, D.Sato, E.O.Balogun, T.Sasaki, M.Nagahama, M.Oda, S.Matsuoka, J.Ohmori, T.Honma, M.Inoue, K.Kita, S.Harada.

ABSTRACT

Recent studies on the respiratory chain of Ascaris suum showed that the mitochondrial NADH-fumarate reductase system composed of complex I, rhodoquinone and complex II plays an important role in the anaerobic energy metabolism of adult A. suum. The system is the major pathway of energy metabolism for adaptation to a hypoxic environment not only in parasitic organisms, but also in some types of human cancer cells. Thus, enzymes of the pathway are potential targets for chemotherapy. We found that flutolanil is an excellent inhibitor for A. suum complex II (IC50 = 0.058 μM) but less effectively inhibits homologous porcine complex II (IC50 = 45.9 μM). In order to account for the specificity of flutolanil to A. suum complex II from the standpoint of structural biology, we determined the crystal structures of A. suum and porcine complex IIs binding flutolanil and its derivative compounds. The structures clearly demonstrated key interactions responsible for its high specificity to A. suum complex II and enabled us to find analogue compounds, which surpass flutolanil in both potency and specificity to A. suum complex II. Structures of complex IIs binding these compounds will be helpful to accelerate structure-based drug design targeted for complex IIs.