PDBsum entry: 3f81

Hydrolase

PDB id: 3f81

Contents

Protein chains

179 a.a. *

Ligands

STT ×2

Waters ×219

* Residue conservation analysis

PDB id:

3f81

Name:

Hydrolase

Title:

Interaction of vhr with sa3

Structure:

Dual specificity protein phosphatase 3. Chain: a, b. Fragment: unp residues 3-185. Synonym: dual specificity protein phosphatase vhr. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: dusp3, vhr. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.90Å R-factor: 0.180 R-free: 0.219

Authors:

S.Wu,T.Mutelin,L.Tautz

Key ref:

S.Wu et al. (2009). Multidentate small-molecule inhibitors of vaccinia H1-related (VHR) phosphatase decrease proliferation of cervix cancer cells. J Med Chem, 52, 6716-6723. PubMed id: 19888758 DOI: 10.1021/jm901016k

Date:

11-Nov-08 Release date: 10-Nov-09

Protein chains

P51452  (DUS3_HUMAN) -  Dual specificity protein phosphatase 3

Seq: 185 a.a.

Struc: 179 a.a.

Enzyme reactions

• Enzyme class 2: E.C.3.1.3.16 - Phosphoprotein phosphatase.
• Reaction: A phosphoprotein + H₂O = a protein + phosphate
• Enzyme class 3: E.C.3.1.3.48 - Protein-tyrosine-phosphatase.
• Reaction: Protein tyrosine phosphate + H₂O = protein tyrosine + phosphate

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

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

 Gene Ontology (GO) functional annotation 

• Cellular component: immunological synapse (4 terms)
• Biological process: dephosphorylation (10 terms)
• Biochemical function: hydrolase activity (6 terms)

reference

DOI no: 10.1021/jm901016k

J Med Chem 52:6716-6723 (2009)

PubMed id: 19888758

Multidentate small-molecule inhibitors of vaccinia H1-related (VHR) phosphatase decrease proliferation of cervix cancer cells.

S.Wu, S.Vossius, S.Rahmouni, A.V.Miletic, T.Vang, J.Vazquez-Rodriguez, F.Cerignoli, Y.Arimura, S.Williams, T.Hayes, M.Moutschen, S.Vasile, M.Pellecchia, T.Mustelin, L.Tautz.

ABSTRACT

Loss of VHR phosphatase causes cell cycle arrest in HeLa carcinoma cells, suggesting that VHR inhibition may be a useful approach to halt the growth of cancer cells. We recently reported that VHR is upregulated in several cervix cancer cell lines as well as in carcinomas of the uterine cervix. Here we report the development of multidentate small-molecule inhibitors of VHR that inhibit its enzymatic activity at nanomolar concentrations and exhibit antiproliferative effects on cervix cancer cells. Chemical library screening was used to identify hit compounds, which were further prioritized in profiling and kinetic experiments. SAR analysis was applied in the search for analogs with improved potency and selectivity, resulting in the discovery of novel inhibitors that are able to interact with both the phosphate-binding pocket and several distinct hydrophobic regions within VHR's active site. This multidentate binding mode was confirmed by X-ray crystallography. The inhibitors decreased the proliferation of cervix cancer cells, while growth of primary normal keratinocytes was not affected. These compounds may be a starting point to develop drugs for the treatment of cervical cancer.