 |
PDBsum entry 6cmp
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
Mechanism of activating mutations and allosteric drug inhibition of the phosphatase shp2.
|
|
|
Authors
|
|
R.A.P.Pádua,
Y.Sun,
I.Marko,
W.Pitsawong,
J.B.Stiller,
R.Otten,
D.Kern.
|
|
|
Ref.
|
|
Nat Commun, 2018,
9,
4507.
|
|
|
PubMed id
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
