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Nanobodies and chemical cross-links advance the structural and functional analysis of PI3Kα.
Hart, Jonathan R; Liu, Xiao; Pan, Chen; Liang, Anyi; Ueno, Lynn; Xu, Yingna; Quezada, Alexandra; Zou, Xinyu; Yang, Su; Zhou, Qingtong; Schoonooghe, Steve; Hassanzadeh-Ghassabeh, Gholamreza; Xia, Tian; Shui, Wenqing; Yang, Dehua; Vogt, Peter K; Wang, Ming-Wei.
Afiliación
  • Hart JR; Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA 92037.
  • Liu X; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai 201203, China.
  • Pan C; National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Liang A; iHuman Institute, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • Ueno L; School of Artificial Intelligence and Automation, Huazhong University of Science and Technology, Wuhan 430074, China.
  • Xu Y; Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA 92037.
  • Quezada A; Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
  • Zou X; Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA 92037.
  • Yang S; School of Artificial Intelligence and Automation, Huazhong University of Science and Technology, Wuhan 430074, China.
  • Zhou Q; Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA 92037.
  • Schoonooghe S; Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
  • Hassanzadeh-Ghassabeh G; Vlaams Instituut voor Biotechnologie, Nanobody Core, Vrije Universiteit Brussel, 1050 Brussels, Belgium.
  • Xia T; Vlaams Instituut voor Biotechnologie, Nanobody Core, Vrije Universiteit Brussel, 1050 Brussels, Belgium.
  • Shui W; School of Artificial Intelligence and Automation, Huazhong University of Science and Technology, Wuhan 430074, China.
  • Yang D; iHuman Institute, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • Vogt PK; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai 201203, China.
  • Wang MW; National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Proc Natl Acad Sci U S A ; 119(38): e2210769119, 2022 09 20.
Article en En | MEDLINE | ID: mdl-36095215
ABSTRACT
Nanobodies and chemical cross-linking were used to gain information on the identity and positions of flexible domains of PI3Kα. The application of chemical cross-linking mass spectrometry (CXMS) facilitated the identification of the p85 domains BH, cSH2, and SH3 as well as their docking positions on the PI3Kα catalytic core. Binding of individual nanobodies to PI3Kα induced activation or inhibition of enzyme activity and caused conformational changes that could be correlated with enzyme function. Binding of nanobody Nb3-126 to the BH domain of p85α substantially improved resolution for parts of the PI3Kα complex, and binding of nanobody Nb3-159 induced a conformation of PI3Kα that is distinct from known PI3Kα structures. The analysis of CXMS data also provided mechanistic insights into the molecular underpinning of the flexibility of PI3Kα.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Dominio Catalítico / Fosfatidilinositol 3-Quinasa Clase I / Fosfatidilinositol 3-Quinasa Clase Ia Límite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2022 Tipo del documento: Article
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Dominio Catalítico / Fosfatidilinositol 3-Quinasa Clase I / Fosfatidilinositol 3-Quinasa Clase Ia Límite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2022 Tipo del documento: Article