6CMQ

Structure of human SHP2 without N-SH2 domain

Summary for 6CMQ

• Entry DOI: 10.2210/pdb6cmq/pdb
• Descriptor: Tyrosine-protein phosphatase non-receptor type 11 (2 entities in total)
• Functional Keywords: protein tyrosine phosphatase, src homology domain 2, open state, active mutant, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 196525.95

Authors

Padua, R.A.P.,Sun, Y.,Marko, I.,Pitsawong, W.,Kern, D. (deposition date: 2018-03-06, release date: 2018-11-14, Last modification date: 2023-10-04)

Primary citation

Padua, R.A.P.,Sun, Y.,Marko, I.,Pitsawong, W.,Stiller, J.B.,Otten, R.,Kern, D.
Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2.
Nat Commun, 9:4507-4507, 2018

PubMed Abstract: Protein tyrosine phosphatase SHP2 functions as a key regulator of cell cycle control, and activating mutations cause several cancers. Here, we dissect the energy landscape of wild-type SHP2 and the oncogenic mutation E76K. NMR spectroscopy and X-ray crystallography reveal that wild-type SHP2 exchanges between closed, inactive and open, active conformations. E76K mutation shifts this equilibrium toward the open state. The previously unknown open conformation is characterized, including the active-site WPD loop in the inward and outward conformations. Binding of the allosteric inhibitor SHP099 to E76K mutant, despite much weaker, results in an identical structure as the wild-type complex. A conformational selection to the closed state reduces drug affinity which, combined with E76K's much higher activity, demands significantly greater SHP099 concentrations to restore wild-type  activity levels. The differences in structural ensembles and drug-binding kinetics of cancer-associated SHP2 forms may stimulate innovative ideas for developing more potent inhibitors for activated SHP2 mutants.

PubMed: 30375376
DOI: 10.1038/s41467-018-06814-w

Experimental method

X-RAY DIFFRACTION (2.9 Å)