Littlefield Peter, Moasser Mark M, Jura Natalia
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
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.
Chem Biol. 2014 Apr 24;21(4):453-458. doi: 10.1016/j.chembiol.2014.02.011. Epub 2014 Mar 20.
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.
人表皮生长因子受体3（HER3）是一种受体酪氨酸激酶，缺乏催化活性，但因其能够变构激活表皮生长因子受体（EGFR）和人表皮生长因子受体2（HER2）而对细胞稳态至关重要。尽管HER3无催化活性，但它能紧密结合三磷酸腺苷（ATP），这暗示了核苷酸结合口袋在调节HER3功能中可能发挥的作用。我们报道了与ATP竞争性抑制剂博舒替尼结合的HER3假激酶的结构。先前解析的结构表明，博舒替尼能与多种激酶结构域构象发生有效相互作用。与HER3形成复合物时，博舒替尼结合到另一种构象上，这种构象与在HER3-ATP复合物中观察到的构象几乎相同。有趣的是，博舒替尼占据ATP结合位点后，通过以膜依赖的方式增加HER3-EGFR异二聚体的亲和力，提高了HER3在体外作为EGFR变构激活剂的能力。
