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Conversion of Bim-BH3 from Activator to Inhibitor of Bak through Structure-Based Design.
Brouwer, Jason M; Lan, Ping; Cowan, Angus D; Bernardini, Jonathan P; Birkinshaw, Richard W; van Delft, Mark F; Sleebs, Brad E; Robin, Adeline Y; Wardak, Ahmad; Tan, Iris K; Reljic, Boris; Lee, Erinna F; Fairlie, W Douglas; Call, Melissa J; Smith, Brian J; Dewson, Grant; Lessene, Guillaume; Colman, Peter M; Czabotar, Peter E.
  • Brouwer JM; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia.
  • Lan P; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia.
  • Cowan AD; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia.
  • Bernardini JP; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia.
  • Birkinshaw RW; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia.
  • van Delft MF; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia.
  • Sleebs BE; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia.
  • Robin AY; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia.
  • Wardak A; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
  • Tan IK; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
  • Reljic B; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia.
  • Lee EF; La Trobe Institute for Molecular Sciences, La Trobe University, Melbourne, VIC 3086, Australia; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3086, Australia.
  • Fairlie WD; La Trobe Institute for Molecular Sciences, La Trobe University, Melbourne, VIC 3086, Australia; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3086, Australia.
  • Call MJ; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia.
  • Smith BJ; La Trobe Institute for Molecular Sciences, La Trobe University, Melbourne, VIC 3086, Australia.
  • Dewson G; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia.
  • Lessene G; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia; Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, VIC 3052, Australia.
  • Colman PM; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia.
  • Czabotar PE; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia. Electronic address: czabotar@wehi.edu.au.
Mol Cell ; 68(4): 659-672.e9, 2017 Nov 16.
Article en En | MEDLINE | ID: mdl-29149594
ABSTRACT
Certain BH3-only proteins transiently bind and activate Bak and Bax, initiating their oligomerization and the permeabilization of the mitochondrial outer membrane, a pivotal step in the mitochondrial pathway to apoptosis. Here we describe the first crystal structures of an activator BH3 peptide bound to Bak and illustrate their use in the design of BH3 derivatives capable of inhibiting human Bak on mitochondria. These BH3 derivatives compete for the activation site at the canonical groove, are the first engineered inhibitors of Bak activation, and support the role of key conformational transitions associated with Bak activation.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Péptidos / Apoptosis / Proteína Destructora del Antagonista Homólogo bcl-2 / Proteína 11 Similar a Bcl2 / Mitocondrias Límite: Animals / Humans Idioma: En Año: 2017 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Péptidos / Apoptosis / Proteína Destructora del Antagonista Homólogo bcl-2 / Proteína 11 Similar a Bcl2 / Mitocondrias Límite: Animals / Humans Idioma: En Año: 2017 Tipo del documento: Article