title: RETRACTED: An ATP-competitive inhibitor modulates the allosteric function of the HER3 pseudokinase.
abstract: Human epidermal growth factor receptor 3 (HER3) is a receptor tyrosine kinase that lacks catalytic activity but is essential for cellular homeostasis due to its ability to allosterically activate EGFR and HER2. Although catalytically inactive, HER3 binds ATP tightly, hinting at a possible role of the nucleotide-binding pocket in modulating HER3 function. We report a structure of the HER3 pseudokinase bound to the ATP-competitive inhibitor bosutinib. Previously solved structures show that bosutinib can potently interact with multiple kinase domain conformations. In complex with HER3, bosutinib binds to yet another conformation, which is nearly identical to that observed in the HER3-ATP complex. Interestingly, occupation of the ATP-binding site by bosutinib improves the ability of HER3 to act as an allosteric activator of EGFR in vitro by increasing the affinity of the HER3-EGFR heterodimer in a membrane-dependent manner.
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Littlefield
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Moasser
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: natalia.jura@ucsf.edu.
authors.forename: Natalia
authors.initials: N
authors.lastname: Jura
mesh_terms: D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000494:Allosteric Regulation / Q000187:drug effects; D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D020893:Receptor, ErbB-3 / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000814:Aniline Compounds; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C471992:bosutinib; D000255:Adenosine Triphosphate; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3