title: Molecular mimicry-based repositioning of nutlin-3 to anti-apoptotic Bcl-2 family proteins.
abstract: The identification of off-target binding of drugs is a key to repositioning drugs to new therapeutic categories. Here we show the universal interactions of the p53 transactivation domain (p53TAD) with various anti-apoptotic Bcl-2 family proteins via a mouse double minute 2 (MDM2) binding motif, which play an important role in transcription-independent apoptotic pathways of p53. Interestingly, our structural studies reveal that the anti-apoptotic Bcl-2 family proteins and MDM2 share a similar mode of interaction with the p53TAD. On the basis of this close molecular mimicry, our NMR results demonstrate that the potent MDM2 antagonists Nutlin-3 and PMI bind to the anti-apoptotic Bcl-2 family proteins in a manner analogous to that with the p53TAD.
authors.affiliation: Medical Proteomics Research Center, KRIBB, Daejeon 305-806, Republic of Korea.
authors.forename: Ji-Hyang
authors.initials: JH
authors.lastname: Ha
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Won
authors.forename: Jae-Sun
authors.initials: JS
authors.lastname: Shin
authors.forename: Mi
authors.initials: M
authors.lastname: Jang
authors.forename: Kyoung-Seok
authors.initials: KS
authors.lastname: Ryu
authors.forename: Kwang-Hee
authors.initials: KH
authors.lastname: Bae
authors.forename: Sung Goo
authors.initials: SG
authors.lastname: Park
authors.forename: Byoung Chul
authors.initials: BC
authors.lastname: Park
authors.forename: Ho Sup
authors.initials: HS
authors.lastname: Yoon
authors.forename: Seung-Wook
authors.initials: SW
authors.lastname: Chi
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D017209:Apoptosis; D002460:Cell Line; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010879:Piperazines / Q000737:chemistry* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry* / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism; D051020:bcl-X Protein / Q000737:chemistry / Q000378:metabolism
chemical_list: D007093:Imidazoles; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; C482205:nutlin 3; D051736:Proto-Oncogene Proteins c-mdm2