2. Academic Validation
  3. Structural Basis for the Binding Selectivity of Human CDY Chromodomains

Structural Basis for the Binding Selectivity of Human CDY Chromodomains

  • Cell Chem Biol. 2020 Jul 16;27(7):827-838.e7. doi: 10.1016/j.chembiol.2020.05.007.
Cheng Dong 1,  Yanli Liu 2,  Tian-Jie Lyu 3,  Serap Beldar 4,  Kelsey N Lamb 5,  Wolfram Tempel 4,  Yanjun Li 4,  Zoey Li 3,  Lindsey I James 5,  Su Qin 6,  Yun Wang 7,  Jinrong Min 8
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
  • 2 College of Pharmaceutical Sciences, Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu 215123, China; Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, Hubei 430079, China.
  • 3 Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Key Laboratory for Neuroscience, Ministry of Education/National Health Commission, Peking University, Beijing 100191, China.
  • 4 Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada.
  • 5 Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 6 Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada; Life Science Research Center, Southern University of Science and Technology, Shenzhen 518055, China. Electronic address: [email protected].
  • 7 Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Key Laboratory for Neuroscience, Ministry of Education/National Health Commission, Peking University, Beijing 100191, China; PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China. Electronic address: [email protected].
  • 8 Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, Hubei 430079, China; Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: [email protected].
PMID: 32470319 DOI: 10.1016/j.chembiol.2020.05.007
Abstract

The CDY (chromodomain on the Y) proteins play an essential role in normal spermatogenesis and brain development. Dysregulation of their expression has been linked to male infertility and various neurological diseases. Like the chromodomains of HP1 and Polycomb, the CDY chromodomains also recognize the lysine-methylated ARKS motif embedded in histone and non-histone proteins. Interestingly, the CDY chromodomains exhibit different binding preferences for the lysine-methylated ARKS motif in different sequence contexts. Here, we present the structural basis for selective binding of CDY1 to H3K9me3 and preferential binding of CDYL2 to H3tK27me3 over H3K27me3. In addition, we use a CDYL1/2-selective compound, UNC4850, to gain further insight into the molecular mechanisms underlying CDYL2 binding specificity. Our work also provides critical implications that CDYL1b's role in the regulation of neural development is dependent on its recognition of the lysine-methylated ARKS motif.

Keywords

CDY; chromodomain; histone H3; neural development; small-molecule inhibitor.

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