PDBsum entry 4z9a

Hydrolase

PDB id: 4z9a

Contents

Protein chain

154 a.a.

Ligands

GOL

SO4 ×2

PMS

Waters ×88

PDB id:

4z9a

Name:

Hydrolase

Title:

Crystal structure of low molecular weight protein tyrosine phosphatase isoform a complexed with phenylmethanesulfonic acid

Structure:

Low molecular weight phosphotyrosine protein phosphatase. Chain: a. Synonym: lmw-ptpase,adipocyte acid phosphatase,low molecular weight cytosolic acid phosphatase,red cell acid phosphatase 1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: acp1. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.10Å R-factor: 0.183 R-free: 0.235

Authors:

D.B.B.Trivella,E.M.B.Fonseca,V.Scorsato,M.P.Dias,R.Aparicio

Key ref:

E.M.Fonseca et al. (2015). Crystal structures of the apo form and a complex of human LMW-PTP with a phosphonic acid provide new evidence of a secondary site potentially related to the anchorage of natural substrates. Bioorg Med Chem Lett, 23, 4462-4471. PubMed id: 26117648 DOI: 10.1016/j.bmc.2015.06.017

Date:

10-Apr-15 Release date: 15-Jul-15

Protein chain

P24666  (PPAC_HUMAN) -  Low molecular weight phosphotyrosine protein phosphatase from Homo sapiens

Seq: 158 a.a.

Struc: 154 a.a.

Enzyme reactions

• Enzyme class 2: E.C.3.1.3.2 - acid phosphatase.
• Reaction: a phosphate monoester + H2O = an alcohol + phosphate
• Enzyme class 3: E.C.3.1.3.48 - protein-tyrosine-phosphatase.
• Reaction: O-phospho-L-tyrosyl-[protein] + H2O = L-tyrosyl-[protein] + 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

reference

DOI no: 10.1016/j.bmc.2015.06.017

Bioorg Med Chem Lett 23:4462-4471 (2015)

PubMed id: 26117648

Crystal structures of the apo form and a complex of human LMW-PTP with a phosphonic acid provide new evidence of a secondary site potentially related to the anchorage of natural substrates.

E.M.Fonseca, D.B.Trivella, V.Scorsato, M.P.Dias, N.L.Bazzo, K.R.Mandapati, F.L.de Oliveira, C.V.Ferreira-Halder, R.A.Pilli, P.C.Miranda, R.Aparicio.

ABSTRACT

Low molecular weight protein tyrosine phosphatases (LMW-PTP, EC 3.1.3.48) are a family of single-domain enzymes with molecular weight up to 18kDa, expressed in different tissues and considered attractive pharmacological targets for cancer chemotherapy. Despite this, few LMW-PTP inhibitors have been described to date, and the structural information on LMW-PTP druggable binding sites is scarce. In this study, a small series of phosphonic acids were designed based on a new crystallographic structure of LMW-PTP complexed with benzylsulfonic acid, determined at 2.1Å. In silico docking was used as a tool to interpret the structural and enzyme kinetics data, as well as to design new analogs. From the synthesized series, two compounds were found to act as competitive inhibitors, with inhibition constants of 0.124 and 0.047mM. We also report the 2.4Å structure of another complex in which LMW-PTP is bound to benzylphosphonic acid, and a structure of apo LMW-PTP determined at 2.3Å resolution. Although no appreciable conformation changes were observed, in the latter structures, amino acid residues from an expression tag were found bound to a hydrophobic region at the protein surface. This regions is neighbored by positively charged residues, adjacent to the active site pocket, suggesting that this region might be not a mere artefact of crystal contacts but an indication of a possible anchoring region for the natural substrate-which is a phosphorylated protein.