title: Structural insights into the dual-targeting mechanism of Nutlin-3.
abstract: Multi-targeting therapy is an emerging strategy of drug discovery to improve therapeutic efficacy, safety and resistance profiles. In this study, we monitored the binding of a potent MDM2 inhibitor Nutlin-3 with anti-apoptotic Bcl-2 family proteins using NMR spectroscopy. Our results showed the universal binding of Nutlin-3 with diverse anti-apoptotic Bcl-2 family proteins. Taken together with the binding data for Nutlin-3 analogs, the structural model of the Bcl-X(L)/Nutlin-3 complex showed that the binding mode of Nutlin-3 resembles that of the Bcl-X(L)/Bcl-2 inhibitors, suggesting the molecular mechanism of transcription-independent mitochondrial apoptosis by Nutlin-3. Finally, our structural comparison provides structural insights into the dual-targeting mechanism of how Nutlin-3 can bind to two different target proteins, MDM2 and anti-apoptotic Bcl-2 family proteins in a similar manner.
authors.affiliation: Medical Proteomics Research Center, KRIBB, Daejeon 305-806, Republic of Korea.
authors.forename: Jae-Sun
authors.initials: JS
authors.lastname: Shin
authors.forename: Ji-Hyang
authors.initials: JH
authors.lastname: Ha
authors.forename: Fahu
authors.initials: F
authors.lastname: He
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Muto
authors.forename: Kyoung-Seok
authors.initials: KS
authors.lastname: Ryu
authors.forename: Ho Sup
authors.initials: HS
authors.lastname: Yoon
authors.forename: Sunghyun
authors.initials: S
authors.lastname: Kang
authors.forename: Sung Goo
authors.initials: SG
authors.lastname: Park
authors.forename: Byoung Chul
authors.initials: BC
authors.lastname: Park
authors.forename: Sang-Un
authors.initials: SU
authors.lastname: Choi
authors.forename: Seung-Wook
authors.initials: SW
authors.lastname: Chi
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D019906:Nuclear Magnetic Resonance, Biomolecular; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D051020:bcl-X Protein / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C482205:nutlin 3; D051736:Proto-Oncogene Proteins c-mdm2