4otw
From Proteopedia
HER3 pseudokinase domain bound to bosutinib
Structural highlights
Disease[ERBB3_HUMAN] Defects in ERBB3 are the cause of lethal congenital contracture syndrome type 2 (LCCS2) [MIM:607598]; also called Israeli Bedouin multiple contracture syndrome type A. LCCS2 is an autosomal recessive neurogenic form of a neonatally lethal arthrogryposis that is associated with atrophy of the anterior horn of the spinal cord. The LCCS2 syndrome is characterized by multiple joint contractures, anterior horn atrophy in the spinal cord, and a unique feature of a markedly distended urinary bladder. The phenotype suggests a spinal cord neuropathic etiology.[1] Function[ERBB3_HUMAN] Binds and is activated by neuregulins and NTAK.[2] Publication Abstract from PubMedHuman 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. An ATP-Competitive Inhibitor Modulates the Allosteric Function of the HER3 Pseudokinase.,Littlefield P, Moasser MM, Jura N Chem Biol. 2014 Mar 18. pii: S1074-5521(14)00069-6. doi:, 10.1016/j.chembiol.2014.02.011. PMID:24656791[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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