title: Crystal structure of human DT-diaphorase: a model for interaction with the cytotoxic prodrug 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB1954).
abstract: The crystal structure of human DT-diaphorase (NAD(P)H oxidoreductase (quinone); EC 1.6.99.2) has been determined to 2.3 A resolution. There are only minor differences in shape and volume between the active sites of the rat and human enzymes and in the hydrophobic environment in the vicinity of the substrate. The isoalloxazine ring of the bound FAD is more buried in the human structure. Molecular modeling was used to examine optimal positions for the antitumor prodrug CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) in both the human and rat enzyme active sites. This suggests that the position of CB1954 in the active site of the human enzyme is very similar to that in the rat, although there are detailed differences in the predicted patterns of hydrogen bonding between side chains and the drug. Some of the differences are a consequence of the shift in position for the FAD molecule and may contribute to the observed differences in rate of the two-electron reduction of CB1954.
authors.affiliation: CRC Biomolecular Structure Unit and CRC Centre for Cancer Therapeutics, The Institute of Cancer Research, Cotswold Road, Sutton, Surrey SM2 5NG, UK.
authors.forename: J V
authors.initials: JV
authors.lastname: Skelly
authors.forename: M R
authors.initials: MR
authors.lastname: Sanderson
authors.forename: D A
authors.initials: DA
authors.lastname: Suter
authors.forename: U
authors.initials: U
authors.lastname: Baumann
authors.forename: M A
authors.initials: MA
authors.lastname: Read
authors.forename: D S
authors.initials: DS
authors.lastname: Gregory
authors.forename: M
authors.initials: M
authors.lastname: Bennett
authors.forename: S M
authors.initials: SM
authors.lastname: Hobbs
authors.forename: S
authors.initials: S
authors.lastname: Neidle
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D001388:Aziridines / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry*; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D001388:Aziridines; D011355:Prodrugs; C100099:tretazicar; D016660:NAD(P)H Dehydrogenase (Quinone)