PDBsum entry 5jwc

Membrane protein

PDB id: 5jwc

Contents

Protein chains

495 a.a.

Ligands

FAD ×2

TRT ×6

4W0 ×4

Metals

_MG ×8

Waters ×448

PDB id:

5jwc

Name:

Membrane protein

Title:

Structure of ndh2 from plasmodium falciparum in complex with ryl-552

Structure:

Nadh dehydrogenase, putative. Chain: a, h. Fragment: unp residues 25-533. Engineered: yes

Source:

Plasmodium falciparum (isolate 3d7). Organism_taxid: 36329. Strain: isolate 3d7. Gene: pfi0735c. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693

Resolution:

2.05Å R-factor: 0.189 R-free: 0.221

Authors:

Y.Yu

Key ref:

Y.Yang et al. (2017). Target Elucidation by Cocrystal Structures of NADH-Ubiquinone Oxidoreductase of Plasmodium falciparum (PfNDH2) with Small Molecule To Eliminate Drug-Resistant Malaria. J Med Chem, 60, 1994-2005. PubMed id: 28195463 DOI: 10.1021/acs.jmedchem.6b01733

Date:

12-May-16 Release date: 22-Mar-17

Protein chains

Q8I302  (Q8I302_PLAF7) -  Type II NADH:ubiquinone oxidoreductase from Plasmodium falciparum (isolate 3D7)

Seq: 533 a.a.

Struc: 495 a.a.

Enzyme reactions

• Enzyme class: E.C.1.6.5.3 - Transferred entry: 7.1.1.2.
• Reaction: NADH + ubiquinone + 5 H⁺(In) = NAD⁺ + ubiquinol + 4 H(+)(Out)

NADH (Bound ligand (Het Group name = FAD) matches with 76.36% similarity) + ubiquinone (Bound ligand (Het Group name = 4W0) matches with 45.95% similarity) + 5 × H(+)(In) = NAD(+) + ubiquinol + 4 × H(+)(Out)

• Cofactor: FMN; Iron-sulfur

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

reference

DOI no: 10.1021/acs.jmedchem.6b01733

J Med Chem 60:1994-2005 (2017)

PubMed id: 28195463

Target Elucidation by Cocrystal Structures of NADH-Ubiquinone Oxidoreductase of Plasmodium falciparum (PfNDH2) with Small Molecule To Eliminate Drug-Resistant Malaria.

Y.Yang, Y.Yu, X.Li, J.Li, Y.Wu, J.Yu, J.Ge, Z.Huang, L.Jiang, Y.Rao, M.Yang.

ABSTRACT

Drug-resistant malarial strains have been continuously emerging recently, which posts a great challenge for the global health. Therefore, new antimalarial drugs with novel targeting mechanisms are urgently needed for fighting drug-resistant malaria. NADH-ubiquinone oxidoreductase of Plasmodium falciparum (PfNDH2) represents a viable target for antimalarial drug development. However, the absence of structural information on PfNDH2 limited rational drug design and further development. Herein, we report high resolution crystal structures of the PfNDH2 protein for the first time in Apo-, NADH-, and RYL-552 (a new inhibitor)-bound states. The PfNDH2 inhibitor exhibits excellent potency against both drug-resistant strains in vitro and parasite-infected mice in vivo via a potential allosteric mechanism. Furthermore, it was found that the inhibitor can be used in combination with dihydroartemisinin (DHA) synergistically. These findings not only are important for malarial PfNDH2 protein-based drug development but could also have broad implications for other NDH2-containing pathogenic microorganisms such as Mycobacterium tuberculosis.