title: Crystal structure of the PDZ domain of mouse Dishevelled 1 and its interaction with CXXC5.
abstract: Dishevelled (Dvl) plays a crucial role in Wnt signaling by interacting with membrane-bound receptors and downstream molecules through its PDZ domain. CXXC5 is one of the key molecules that interacts with Dvl and negatively regulates the Wnt/β-catenin pathway in osteoblast differentiation. Recently, the Dvl-CXXC5 interaction has been identified as an excellent target for osteoporosis treatment. Therefore, it is desirable to have detailed structural information for the Dvl-CXXC5 interaction. Although solution structures of the Dvl1 PDZ domain have been reported, a high-resolution crystal structure would provide detailed sidechain information that is essential for drug development. Here, we determined the first crystal structure of the Dvl-1 PDZ domain at a resolution of 1.76 Å, and compared it with its previously reported solution structure. The Dvl1 PDZ domain crystal belonged to the space group H32 with unit-cell parameters a = b = 72.837, c = 120.616, α = β = 90.00, γ = 120.00. The crystal structure of Dvl1 PDZ shared its topology with the previously reported structure determined by nuclear magnetic resonance (NMR); however, the crystal structure was quite different from the solution structure in both the secondary structural region and the ligand-binding pocket. Molecular modeling based on NMR and X-ray crystallographic data yielded detailed information about the Dvl1/CXXC5 interaction, which will be useful for designing inhibitors.
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-740, South Korea.
authors.forename: Inhwan
authors.initials: I
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-740, South Korea.
authors.forename: Sooho
authors.initials: S
authors.lastname: Choi
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-740, South Korea.
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Yun
authors.affiliation: Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, South Korea; Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, South Korea.
authors.forename: Seol Hwa
authors.initials: SH
authors.lastname: Seo
authors.affiliation: Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, South Korea; Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, South Korea.
authors.forename: Sehee
authors.initials: S
authors.lastname: Choi
authors.affiliation: Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, South Korea; Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, South Korea.
authors.forename: Kang-Yell
authors.initials: KY
authors.lastname: Choi
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-740, South Korea. Electronic address: wtlee@yonsei.ac.kr.
authors.forename: Weontae
authors.initials: W
authors.lastname: Lee
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D003460:Crystallization; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins; D000072261:Dishevelled Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D054731:PDZ Domains; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid; D012996:Solutions; D014157:Transcription Factors; D060449:Wnt Signaling Pathway
chemical_list: C000601091:CXXC5 protein, mouse; D004268:DNA-Binding Proteins; D000072261:Dishevelled Proteins; C000606579:Dvl1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D010455:Peptides; D012996:Solutions; D014157:Transcription Factors
keywords: CXXC5; Dvl-1; PDZ domain; Wnt signaling; X-ray crystallography