PDBsum entry 4zvm

Oxidoreductase/oxidoreductase inhibitor

PDB id: 4zvm

Contents

Protein chains

230 a.a.

Ligands

FAD ×2

DM2 ×2

Metals

_ZN ×2

Waters ×341

PDB id:

4zvm

Name:

Oxidoreductase/oxidoreductase inhibitor

Title:

Oxidized quinone reductase 2 in complex with doxorubicin

Structure:

Ribosyldihydronicotinamide dehydrogenase [quinone]. Chain: a, b. Synonym: nrh dehydrogenase [quinone] 2,nrh:quinone oxidoreductase 2, quinone reductase 2,qr2. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: nqo2, nmor2. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.97Å R-factor: 0.172 R-free: 0.229

Authors:

K.K.Leung,B.H.Shilton

Key ref:

K.K.Leung and B.H.Shilton (2015). Binding of DNA-Intercalating Agents to Oxidized and Reduced Quinone Reductase 2. Biochemistry, 54, 7438-7448. PubMed id: 26636353 DOI: 10.1021/acs.biochem.5b00884

Date:

18-May-15 Release date: 30-Mar-16

Protein chains

P16083  (NQO2_HUMAN) -  Ribosyldihydronicotinamide dehydrogenase [quinone] from Homo sapiens

Seq: 231 a.a.

Struc: 230 a.a.*

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

Enzyme reactions

• Enzyme class: E.C.1.10.5.1 - ribosyldihydronicotinamide dehydrogenase (quinone).
• Reaction: 1-(beta-D-ribofuranosyl)-1,4-dihydronicotinamide + a quinone + H⁺ = beta-nicotinamide D-riboside + a quinol
• Cofactor: FAD; Zn(2+)

FAD (Bound ligand (Het Group name = FAD) corresponds exactly) Zn(2+)

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

reference

DOI no: 10.1021/acs.biochem.5b00884

Biochemistry 54:7438-7448 (2015)

PubMed id: 26636353

Binding of DNA-Intercalating Agents to Oxidized and Reduced Quinone Reductase 2.

K.K.Leung, B.H.Shilton.

ABSTRACT

Quinone reductase 2 (NQO2) is an enzyme that might have intracellular signaling functions. NQO2 can exist in either an oxidized state or a reduced state, and binding of compounds to one or both of these states inhibits enzymatic activity and could also affect intracellular signaling. A wide range of planar aromatic compounds bind NQO2, and we have identified three DNA-intercalating agents [ethidium bromide, acridine orange (AO), and doxorubicin] as novel nanomolar inhibitors of NQO2. Ethidium and AO, which carry a positive charge in their aromatic ring systems, bound reduced NQO2 with an affinity 50-fold higher than that of oxidized NQO2, while doxorubicin bound only oxidized NQO2. Crystallographic analyses of oxidized NQO2 in complex with the inhibitors indicated that the inhibitors were situated deep in the active site. The aromatic faces were sandwiched between the isoalloxazine ring of FAD and the phenyl ring of F178, with their edges making direct contact with residues lining the active site. In reduced NQO2, ethidium and AO occupied a more peripheral position in the active site, allowing several water molecules to interact with the polar end of the negatively charged isoalloxazine ring. We also showed that AO inhibited NQO2 at a nontoxic concentration in cells while ethidium was less effective at inhibiting NQO2 in cells. Together, this study shows that reduced NQO2 has structural and electrostatic properties that yield a preference for binding of planar, aromatic, and positively charged molecules that can also function as DNA-intercalating agents.