title: Structural and functional analyses of minimal phosphopeptides targeting the polo-box domain of polo-like kinase 1.
abstract: Polo-like kinase-1 (Plk1) has a pivotal role in cell proliferation and is considered a potential target for anticancer therapy. The noncatalytic polo-box domain (PBD) of Plk1 forms a phosphoepitope binding module for protein-protein interaction. Here, we report the identification of minimal phosphopeptides that specifically interact with the PBD of human PLK1, but not those of the closely related PLK2 and PLK3. Comparative binding studies and analyses of crystal structures of the PLK1 PBD in complex with the minimal phosphopeptides revealed that the C-terminal SpT dipeptide functions as a high-affinity anchor, whereas the N-terminal residues are crucial for providing specificity and affinity to the interaction. Inhibition of the PLK1 PBD by phosphothreonine mimetic peptides was sufficient to induce mitotic arrest and apoptotic cell death. The mode of interaction between the minimal peptide and PBD may provide a template for designing therapeutic agents that target PLK1.
authors: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Sang-Moon
authors: SM
authors: Yun
authors: Tinoush
authors: T
authors: Moulaei
authors: Dan
authors: D
authors: Lim
authors: Jeong K
authors: JK
authors: Bang
authors: Jung-Eun
authors: JE
authors: Park
authors: Shilpa R
authors: SR
authors: Shenoy
authors: Fa
authors: F
authors: Liu
authors: Young H
authors: YH
authors: Kang
authors: Chenzhong
authors: C
authors: Liao
authors: Nak-Kyun
authors: NK
authors: Soung
authors: Sunhee
authors: S
authors: Lee
authors: Do-Young
authors: DY
authors: Yoon
authors: Yoongho
authors: Y
authors: Lim
authors: Dong-Hee
authors: DH
authors: Lee
authors: Akira
authors: A
authors: Otaka
authors: Ettore
authors: E
authors: Appella
authors: James B
authors: JB
authors: McMahon
authors: Marc C
authors: MC
authors: Nicklaus
authors: Terrence R
authors: TR
authors: Burke
authors: Michael B
authors: MB
authors: Yaffe
authors: Alexander
authors: A
authors: Wlodawer
authors: Kyung S
authors: KS
authors: Lee
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D001667:Binding, Competitive; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010748:Phosphopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013816:Thermodynamics; D013912:Threonine / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D010748:Phosphopeptides; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D013912:Threonine; D000097869:Polo-Like Kinase 1