title: Protein grafting of p53TAD onto a leucine zipper scaffold generates a potent HDM dual inhibitor.
abstract: Reactivation of the p53 pathway by a potential therapeutic antagonist, which inhibits HDM2 and HDMX, is an attractive strategy for drug development in oncology. Developing blockers towards conserved hydrophobic pockets of both HDMs has mainly focused on small synthetic compounds; however, this approach has proved challenging. Here we describe an approach to generate a potent HDM dual inhibitor, p53LZ2, by rational protein grafting of the p53 transactivation domain onto a homodimeric leucine zipper. p53LZ2 shows tight binding affinity to both HDMs compared with wild-type p53 in vitro. X-ray crystallographic, comparative modelling and small-angle X-ray scattering studies of p53LZ2-HDM complexes show butterfly-shaped structures. A cell-permeable TAT-p53LZ2 effectively inhibits the cancer cell growth in wild-type but not mutant p53 by arresting cell cycle and inducing apoptosis in vitro. Thus, p53LZ2, designed by rational grafting, shows a potential therapeutic approach against cancer.
authors.affiliation: Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd., Suwon 443-803, South Korea.
authors.forename: Jung-Hoon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd., Suwon 443-803, South Korea.
authors.forename: Eunji
authors.initials: E
authors.lastname: Kang
authors.affiliation: Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd., Suwon 443-803, South Korea.
authors.forename: Jungmin
authors.initials: J
authors.lastname: Lee
authors.affiliation: Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd., Suwon 443-803, South Korea.
authors.forename: Jungmin
authors.initials: J
authors.lastname: Kim
authors.affiliation: Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd., Suwon 443-803, South Korea.
authors.forename: Kyoung Hu
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd., Suwon 443-803, South Korea.
authors.forename: Jieun
authors.initials: J
authors.lastname: Han
authors.affiliation: Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd., Suwon 443-803, South Korea.
authors.forename: Hye Yoon
authors.initials: HY
authors.lastname: Kang
authors.affiliation: Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd., Suwon 443-803, South Korea.
authors.forename: Soshin
authors.initials: S
authors.lastname: Ahn
authors.affiliation: Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd., Suwon 443-803, South Korea.
authors.forename: Youngmi
authors.initials: Y
authors.lastname: Oh
authors.affiliation: Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd., Suwon 443-803, South Korea.
authors.forename: Dongkyu
authors.initials: D
authors.lastname: Shin
authors.affiliation: Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd., Suwon 443-803, South Korea.
authors.forename: Kyeyeon
authors.initials: K
authors.lastname: Hur
authors.affiliation: Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd., Suwon 443-803, South Korea.
authors.forename: Su Young
authors.initials: SY
authors.lastname: Chae
authors.affiliation: Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd., Suwon 443-803, South Korea.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Song
authors.affiliation: 1] Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd., Suwon 443-803, South Korea [2] Bio Research Center, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd., Suwon 443-803, South Korea.
authors.forename: Yong-In
authors.initials: YI
authors.lastname: Kim
authors.affiliation: Bio Research Center, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd., Suwon 443-803, South Korea.
authors.forename: Jae Chan
authors.initials: JC
authors.lastname: Park
authors.affiliation: Bio Therapeutics Laboratory, Samsung Advanced Institute of Technology (SAIT), Samsung Electronics Co. Ltd., Suwon 443-803, South Korea.
authors.forename: Jae Il
authors.initials: JI
authors.lastname: Lee
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000235:genetics; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D016350:Leucine Zippers / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D056004:Molecular Dynamics Simulation; D046912:Multiprotein Complexes / Q000648:ultrastructure; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D015202:Protein Engineering; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000494:pharmacology* / Q000648:ultrastructure; D016415:Sequence Alignment; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics* / Q000648:ultrastructure
chemical_list: D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2