PDBsum entry 6h8s

Hydrolase

PDB id: 6h8s

Contents

Protein chain

291 a.a.

Ligands

FSZ

Waters ×277

PDB id:

6h8s

Name:

Hydrolase

Title:

Crystal structure of the mouse protein tyrosine phosphatase ptpn5 (step) in complex with compound bi-0314

Structure:

Tyrosine-protein phosphatase non-receptor type 5. Chain: a. Synonym: neural-specific protein-tyrosine phosphatase,striatum- enriched protein-tyrosine phosphatase,step. Engineered: yes

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Gene: ptpn5. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.77Å R-factor: 0.183 R-free: 0.212

Authors:

D.Fiegen,G.Schnapp

Key ref:

C.S.Tautermann et al. (2019). Allosteric Activation of Striatal-Enriched Protein Tyrosine Phosphatase (STEP, PTPN5) by a Fragment-like Molecule. J Med Chem, 62, 306-316. PubMed id: 30207464 DOI: 10.1021/acs.jmedchem.8b00857

Date:

03-Aug-18 Release date: 26-Sep-18

Protein chain

P54830  (PTN5_MOUSE) -  Tyrosine-protein phosphatase non-receptor type 5 from Mus musculus

Seq: 541 a.a.

Struc: 291 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

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

DOI no: 10.1021/acs.jmedchem.8b00857

J Med Chem 62:306-316 (2019)

PubMed id: 30207464

Allosteric Activation of Striatal-Enriched Protein Tyrosine Phosphatase (STEP, PTPN5) by a Fragment-like Molecule.

C.S.Tautermann, F.Binder, F.H.Büttner, C.Eickmeier, D.Fiegen, U.Gross, M.A.Grundl, R.Heilker, S.Hobson, S.Hoerer, A.Luippold, V.Mack, F.Montel, S.Peters, S.Bhattacharya, N.Vaidehi, G.Schnapp, S.Thamm, M.Zeeb.

ABSTRACT

Protein tyrosine phosphatase non-receptor type 5 (PTPN5, STEP) is a brain specific phosphatase that regulates synaptic function and plasticity by modulation of N-methyl-d-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking. Dysregulation of STEP has been linked to neurodegenerative and neuropsychiatric diseases, highlighting this enzyme as an attractive therapeutic target for drug discovery. Selective targeting of STEP with small molecules has been hampered by high conservation of the active site among protein tyrosine phosphatases. We report the discovery of the first small molecule allosteric activator for STEP that binds to the phosphatase domain. Allosteric binding is confirmed by both X-ray and ¹⁵N NMR experiments, and specificity has been demonstrated by an enzymatic test cascade. Molecular dynamics simulations indicate stimulation of enzymatic activity by a long-range allosteric mechanism. To allow the scientific community to make use of this tool, we offer to provide the compound in the course of an open innovation initiative.