title: Binding of the anticancer prodrug CB1954 to the activating enzyme NQO2 revealed by the crystal structure of their complex.
abstract: CB1954 is an attractive prodrug for directed-enzyme prodrug therapy (DEPT) and a conventional prodrug against tumors in which the enzyme NQO2 is highly expressed. We have determined the crystal structure of the NQO2-CB1954 complex to 2.0 A resolution. The binding of the prodrug is governed by hydrophobic forces, while two key electrostatic contacts determine the specific orientation of the ligand. The structure also reveals an unfavorable interaction, therefore suggesting possible avenues for DEPT-tailored engineering studies.
authors.affiliation: School of Pharmacy and The Institute of Infection, Immunity and Inflammation, Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.
authors.forename: Majed
authors.initials: M
authors.lastname: AbuKhader
authors.forename: John
authors.initials: J
authors.lastname: Heap
authors.forename: Cristina
authors.initials: C
authors.lastname: De Matteis
authors.forename: Barrie
authors.initials: B
authors.lastname: Kellam
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Doughty
authors.forename: Nigel
authors.initials: N
authors.lastname: Minton
authors.forename: Massimo
authors.initials: M
authors.lastname: Paoli
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D001388:Aziridines / Q000737:chemistry*; D003460:Crystallization; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D008968:Molecular Conformation; D011355:Prodrugs / Q000737:chemistry*; D011485:Protein Binding; D011808:Quinone Reductases / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D001388:Aziridines; D011355:Prodrugs; C100099:tretazicar; C419642:NRH - quinone oxidoreductase2; D011808:Quinone Reductases