Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2.

Pádua RAP, Sun Y, Marko I, Pitsawong W, Stiller JB, Otten R, Kern D, Nat Commun 9(1):4507 (2018) Europe PMC

SASDEP4 – Protein tyrosine phosphatase SHP2 with E76K activating mutation

Tyrosine-protein phosphatase non-receptor type 11 E76K
MWexperimental 53 kDa
MWexpected 61 kDa
log I(s) 1.42×102 1.42×101 1.42×100 1.42×10-1
Tyrosine-protein phosphatase non-receptor type 11 E76K small angle scattering data  s, nm-1
ln I(s)
Tyrosine-protein phosphatase non-receptor type 11 E76K Guinier plot ln 1.43×102 Rg: 2.9 nm 0 (2.9 nm)-2 s2
(sRg)2I(s)/I(0)
Tyrosine-protein phosphatase non-receptor type 11 E76K Kratky plot 1.104 0 √3 sRg
p(r)
Tyrosine-protein phosphatase non-receptor type 11 E76K pair distance distribution function Rg: 3.0 nm 0 Dmax: 9.5 nm

Data validation

Fits and models

log I(s)
 s, nm-1
Tyrosine-protein phosphatase non-receptor type 11 E76K ALLOSMOD model
Synchrotron SAXS data from solutions of Protein tyrosine phosphatase SHP2 with E76K activating mutation in 50 mM ADA, 2 mM TCEP, pH 6.5 were collected on the BL4-2 beam line at the Stanford Synchrotron Radiation Lightsource (SSRL; Stanford, CA, USA) using a Rayonix MX225-HE detector at a sample-detector distance of 1.7 m and at a wavelength of λ = 0.1127 nm (l(s) vs s, where s = 4πsinθ/λ, and 2θ is the scattering angle). Solute concentrations ranging between 0.8 and 12.2 mg/ml were measured at 20°C. 10 successive 1 second frames were collected. The data were normalized to the intensity of the transmitted beam and radially averaged; the scattering of the solvent-blank was subtracted. The low angle data collected at lower concentration were merged with the highest concentration high angle data to yield the final composite scattering curve.

Tyrosine-protein phosphatase non-receptor type 11 E76K (SHP2 E76K)
Mol. type   Protein
Organism   Homo sapiens
Olig. state   Monomer
Mon. MW   60.9 kDa
 
UniProt   Q06124-2 (1-529)
Sequence   FASTA
 
PDB ID   6CMQ