PDBsum entry 2cmc

Hydrolase

PDB id: 2cmc

Contents

Protein chain

286 a.a. *

Ligands

DFM

SO4

BOG

Waters ×178

* Residue conservation analysis

PDB id:

2cmc

Name:

Hydrolase

Title:

Structural basis for inhibition of protein tyrosine phosphatase 1b by isothiazolidinone heterocyclic phosphonate mimetics

Structure:

Tyrosine-protein phosphatase non-receptor type 1. Chain: a. Fragment: catalytic domain, residues 1-298. Synonym: protein tyrosine phosphatase 1b. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.20Å R-factor: 0.209 R-free: 0.263

Authors:

P.J.Ala,L.Gonneville,M.C.Hillman,M.Becker-Pasha,M.Wei,B.G.Reid, R.Klabe,E.W.Yue,B.Wayland,B.Douty,A.P.Combs,P.Polam,Z.Wasserman, M.Bower,T.C.Burn,G.F.Hollis,R.Wynn

Key ref:

P.J.Ala et al. (2006). Structural basis for inhibition of protein-tyrosine phosphatase 1B by isothiazolidinone heterocyclic phosphonate mimetics. J Biol Chem, 281, 32784-32795. PubMed id: 16916797 DOI: 10.1074/jbc.M606873200

Date:

04-May-06 Release date: 17-Aug-06

Protein chain

P18031  (PTN1_HUMAN) -  Tyrosine-protein phosphatase non-receptor type 1 from Homo sapiens

Seq: 435 a.a.

Struc: 286 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

DOI no: 10.1074/jbc.M606873200

J Biol Chem 281:32784-32795 (2006)

PubMed id: 16916797

Structural basis for inhibition of protein-tyrosine phosphatase 1B by isothiazolidinone heterocyclic phosphonate mimetics.

P.J.Ala, L.Gonneville, M.C.Hillman, M.Becker-Pasha, M.Wei, B.G.Reid, R.Klabe, E.W.Yue, B.Wayland, B.Douty, P.Polam, Z.Wasserman, M.Bower, A.P.Combs, T.C.Burn, G.F.Hollis, R.Wynn.

ABSTRACT

Crystal structures of protein-tyrosine phosphatase 1B in complex with compounds bearing a novel isothiazolidinone (IZD) heterocyclic phosphonate mimetic reveal that the heterocycle is highly complementary to the catalytic pocket of the protein. The heterocycle participates in an extensive network of hydrogen bonds with the backbone of the phosphate-binding loop, Phe(182) of the flap, and the side chain of Arg(221). When substituted with a phenol, the small inhibitor induces the closed conformation of the protein and displaces all waters in the catalytic pocket. Saturated IZD-containing peptides are more potent inhibitors than unsaturated analogs because the IZD heterocycle and phenyl ring directly attached to it bind in a nearly orthogonal orientation with respect to each other, a conformation that is close to the energy minimum of the saturated IZD-phenyl moiety. These results explain why the heterocycle is a potent phosphonate mimetic and an ideal starting point for designing small nonpeptidic inhibitors.

Selected figure(s)

Figure 2.
FIGURE 2. Crystal structure of PTP1B/1. a, superposition of the bound conformations of the phosphonate mimetics of compounds 1, 5, and 1G7G. Note the IZD heterocycle of 1 mimics the interactions of DFMP and CMBA, and it displaces four waters. b, stereo view of the 2F[o] - F[c] simulated annealed omit map (contoured at 1 ) and atomic model for PTP1B/1. The inhibitor was omitted from the model prior to a cycle of simulated annealing and was not used in the calculation of phases. c, stereo view of 1 (ball-and-stick) bound in the A site. Dashed lines indicate 10 potential hydrogen bonds between the inhibitor and residues in the active site.

Figure 6.
FIGURE 6. Bound conformations of saturated and unsaturated IZD-phenyl moieties. a, the relative angle between the unsaturated IZD and phenyl rings of 1 is 70-75°. b, superposition of the unsaturated IZD 1 (stick bonds) and the saturated (S)-IZD-phenyl moiety of 2 (ball-and-stick). Note the phenyl ring and heteroatoms of IZD bind in the same position whether or not the heterocycle is reduced.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2006, 281, 32784-32795) copyright 2006.

Figures were selected by the author.