PDBsum entry 6cmp

Hydrolase

PDB id: 6cmp

Contents

Protein chains

498 a.a.

Waters ×763

PDB id:

6cmp

Name:

Hydrolase

Title:

Closed structure of inactive shp2 mutant c459e

Structure:

Tyrosine-protein phosphatase non-receptor type 11. Chain: a, b. Synonym: protein-tyrosine phosphatase 1d,ptp-1d,protein-tyrosine phosphatase 2c,ptp-2c,sh-ptp2,shp2,sh-ptp3. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ptpn11, ptp2c, shptp2. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.80Å R-factor: 0.202 R-free: 0.231

Authors:

R.A.P.Padua,Y.Sun,I.Marko,W.Pitsawong,D.Kern

Key ref:

R.A.P.Pádua et al. (2018). Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2. Nat Commun, 9, 4507. PubMed id: 30375376

Date:

06-Mar-18 Release date: 14-Nov-18

Protein chains

Q06124  (PTN11_HUMAN) -  Tyrosine-protein phosphatase non-receptor type 11 from Homo sapiens

Seq: 593 a.a.

Struc: 498 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.3.1.3.48 - protein-tyrosine-phosphatase.
• Reaction: O-phospho-L-tyrosyl-[protein] + H2O = L-tyrosyl-[protein] + phosphate

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Key reference

Nat Commun 9:4507 (2018)

PubMed id: 30375376

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

R.A.P.Pádua, Y.Sun, I.Marko, W.Pitsawong, J.B.Stiller, R.Otten, D.Kern.

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.