Abstract
Effective inactivation of the HER2-HER3 tumor driver has remained elusive because of the challenging attributes of the pseudokinase HER3. We report a structure-function study of constitutive HER2-HER3 signaling to identify opportunities for targeting. The allosteric activation of the HER2 kinase domain (KD) by the HER3 KD is required for tumorigenic signaling and can potentially be targeted by allosteric inhibitors. ATP binding within the catalytically inactive HER3 KD provides structural rigidity that is important for signaling, but this is mimicked, not opposed, by small molecule ATP analogs, reported here in a bosutinib-bound crystal structure. Mutational disruption of ATP binding and molecular dynamics simulation of the apo KD of HER3 identify a conformational coupling of the ATP pocket with a hydrophobic AP-2 pocket, analogous to EGFR, that is critical for tumorigenic signaling and feasible for targeting. The value of these potential target sites is confirmed in tumor growth assays using gene replacement techniques.
| Original language | English |
|---|---|
| Article number | 110291 |
| Journal | Cell Reports |
| Volume | 38 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 1 Feb 2022 |
Bibliographical note
Funding Information:This work was supported by National Institutes of Health grants CA122216 (to M.M.M.) and GM109176 (to N.J.), the Susan G. Komen Foundation (grant CCR14299947 to N.J.; postdoctoral fellowship grants to M.R.C.), the American Association for Cancer Research-Genentech BioOncology Fellowship (to M.R.C.), and the Ramón Areces Foundation (to A.R.S.). The authors would like to thank James Lee for his technical assistance with cell-based studies.
Publisher Copyright:
© 2021 The Authors
