Structural reorganization of SHP2 by oncogenic mutations and implications for oncoprotein resistance to allosteric inhibition

• DOI: 10.1038/s41467-018-06823-9
• Publication Date: 2018-10-24T09:01:05Z
• Authors: Jonathan R. LaRoc...; Michelle Fodor; Vidyasiri Vemulap...; Morvarid Mohseni; Ping Wang; Travis Stams; Matthew J. LaMarche; Rajiv Chopra; Michael G. Acker; Stephen C. Blacklow
• Keywords: PTPN11

Activating mutations in PTPN11, encoding the cytosolic protein tyrosine phosphatase SHP2, result developmental disorders and act as oncogenic drivers patients with hematologic cancers. The allosteric inhibitor SHP099 stabilizes wild-type SHP2 enzyme an autoinhibited conformation that is itself destabilized by mutations. Here, we report impact of highly activated most frequently observed mutation, E76K, on structure investigate effect E76K other inhibition SHP099. SHP2E76K adopts open but can be restored to closed, conformation, near-identical unoccupied enzyme, when complexed inhibitory activity against variants vitro cells scales inversely activating strength indicating either oncoselective or vastly more potent inhibitors will necessary suppress signaling strongly cancer.