Invited ReviewErbB/HER protein-tyrosine kinases: Structures and small molecule inhibitors
Graphical abstract
Section snippets
Biology of the ErbB/HER family of receptors
The ErbB/HER receptor protein-tyrosine kinases are ubiquitously expressed in epithelial, mesenchymal, cardiac, and neuronal cells and in their cellular progenitors [1]. This group of receptors, which includes the epidermal growth factor receptor (EGFR), is among the most studied cell signaling families in biology. They regulate apoptosis, cell cycle progression, differentiation, development, and transcription. EGFR was the first receptor to be characterized as a protein-tyrosine kinase, which
Receptor homo and heterodimers
Ullrich et al. were the first to determine the amino acid sequence of a receptor protein-tyrosine kinase (EGFR) using cDNA sequence analysis [10]. They hypothesized that the receptor consisted of an extracellular domain, a single hydrophobic transmembrane segment, and an intracellular domain with protein kinase activity. This hypothesis has stood the test of time and fundamentally applies to all receptor protein kinases. The ErbB family of protein kinases consists of a glycosylated
Properties of the small and large lobes
The ErbB/HER protein kinase domains have a small amino-terminal lobe and large carboxyterminal lobe first described by Knighton et al. for PKA (Fig. 3) [28]. The two lobes form a cleft that serves as a docking site for ATP. The small lobe contains a conserved glycine-rich (GxGxxG) ATP-phosphate-binding loop, sometimes called the P-loop, which is the most flexible part of the small lobe. This loop is near the phosphates of the ATP substrate. The β1 and β2-strands of the N-lobe harbor the adenine
Binding pocket for ATP and small molecule inhibitors
The glycine-rich loop, or P-loop, occurs universally in protein kinases and consists of a canonical GxGxxΦG sequence where Φ refers to a hydrophobic residue. This sequence in the ErbB family is composed of GSGAFG (Table 2). The P-loop, which forms a lid above the ATP phosphates, is characteristically one of the most mobile portions of the protein kinase domain. This mobility may be due to the requirement that the enzyme binds ATP and then releases ADP following catalysis. In PKA, the second
Phosphoryl transfer transition states
The catalytic mechanisms of protein kinases have been addressed by steady-state and transient kinetics, site specific mutations, quantum mechanical and molecular mechanics simulations, X-ray crystallography, and NMR spectroscopy. Most studies have been performed with PKA, and there is a general consensus that these fundamentals will hold for other protein kinases. However, each class of protein kinase is expected to exhibit its unique variations from the reaction template. The transfer of the
Mutant ERBB1 oncogenic activation
ErbB1/EGFR plays an important role in the pathogenesis of many lung cancers. Herbst et al. reported that EGFR kinase-domain mutations occur in a range of 10–40% of lung cancer samples [75]. The incidence of EGFR kinase-domain mutations is about 10% in Caucasian populations and 30–40% in Asian patients. About 10% of unselected patients with NSCLC exhibited rapid and often dramatic responses to gefitinib [76]. In 2004, three groups compared the tumors of patients who responded to gefitinib with
Epilog
The ErbB family of receptor protein-tyrosine kinases participates in the pathogenesis of several common malignancies listed in Section 1.2. Several small molecule ErbB kinase domain inhibitors have been approved by the FDA for the treatment of lung cancer (afatinib, erlotinib, and lapatinib) and breast cancer (lapatinib). Furthermore several biopharmaceutical agents have been approved for the treatment of breast (pertuzumab, trastuzumab, and ado-trastuzumab emtansine) and colorectal cancer
Conflict of interest
The author is unaware of any affiliations, memberships, or financial holdings that might be perceived as affecting the objectivity of this review.
Acknowledgments
The author thanks Prof. John Kuriyan for providing the protein data bank file for the EGFR asymmetric dimer. He also thanks Laura M. Roskoski for providing editorial and bibliographic assistance.
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