6CRG

Crystal Structure of Shp2 E76K GOF Mutant in complex with SHP099

Summary for 6CRG

• Entry DOI: 10.2210/pdb6crg/pdb
• Related: 6CRF
• Descriptor: Tyrosine-protein phosphatase non-receptor type 11, 6-(4-azanyl-4-methyl-piperidin-1-yl)-3-[2,3-bis(chloranyl)phenyl]pyrazin-2-amine, SULFATE ION, ... (5 entities in total)
• Functional Keywords: shp2, ptpn11, protein tyrosine phosphatase, e76k, gain of function mutant, allosteric inhibitor, hydrolase-hydrolase inhibitor complex, phosphatase, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 122175.27

Authors

Stams, T.,Fodor, M. (deposition date: 2018-03-17, release date: 2018-11-07, Last modification date: 2023-10-04)

Primary citation

LaRochelle, J.R.,Fodor, M.,Vemulapalli, V.,Mohseni, M.,Wang, P.,Stams, T.,LaMarche, M.J.,Chopra, R.,Acker, M.G.,Blacklow, S.C.
Structural reorganization of SHP2 by oncogenic mutations and implications for oncoprotein resistance to allosteric inhibition.
Nat Commun, 9:4508-4508, 2018

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

PubMed: 30375388
DOI: 10.1038/s41467-018-06823-9

Experimental method

X-RAY DIFFRACTION (2.75 Å)