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PDBsum entry 2cnh

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Hydrolase PDB id
2cnh
Jmol
Contents
Protein chain
297 a.a.
Ligands
IZB
Metals
_CA
Waters ×275

References listed in PDB file
Key reference
Title Structural insights into the design of nonpeptidic isothiazolidinone-Containing inhibitors of protein-Tyrosine phosphatase 1b.
Authors P.J.Ala, L.Gonneville, M.Hillman, M.Becker-Pasha, E.W.Yue, B.Douty, B.Wayland, P.Polam, M.L.Crawley, E.Mclaughlin, R.B.Sparks, B.Glass, A.Takvorian, A.P.Combs, T.C.Burn, G.F.Hollis, R.Wynn.
Ref. J Biol Chem, 2006, 281, 38013-38021. [DOI no: 10.1074/jbc.M607913200]
PubMed id 17028182
Abstract
Structural analyses of the protein-tyrosine phosphatase 1B (PTP1B) active site and inhibitor complexes have aided in optimization of a peptide inhibitor containing the novel (S)-isothiazolidinone (IZD) phosphonate mimetic. Potency and permeability were simultaneously improved by replacing the polar peptidic backbone of the inhibitor with nonpeptidic moieties. The C-terminal primary amide was replaced with a benzimidazole ring, which hydrogen bonds to the carboxylate of Asp(48), and the N terminus of the peptide was replaced with an aryl sulfonamide, which hydrogen bonds to Asp(48) and the backbone NH of Arg(47) via a water molecule. Although both substituents retain the favorable hydrogen bonding network of the peptide scaffold, their aryl rings interact weakly with the protein. The aryl ring of benzimidazole is partially solvent exposed and only participates in van der Waals interactions with Phe(182) of the flap. The aryl ring of aryl sulfonamide adopts an unexpected conformation and only participates in intramolecular pi-stacking interactions with the benzimidazole ring. These results explain the flat SAR for substitutions on both rings and the reason why unsubstituted moieties were selected as candidates. Finally, substituents ortho to the IZD heterocycle on the aryl ring of the IZD-phenyl moiety bind in a small narrow site adjacent to the primary phosphate binding pocket. The crystal structure of an o-chloro derivative reveals that chlorine interacts extensively with residues in the small site. The structural insights that have led to the discovery of potent benzimidazole aryl sulfonamide o-substituted derivatives are discussed in detail.
Figure 3.
FIGURE 3. Crystal structure of PTP1B/1. The proximal DFMP moiety of 1 (ball-and-stick) binds at the center of the phosphate binding loop (thick bonds); the C-terminal amide and adjacent amide NHs hydrogen bond (dashed lines) to the carboxylate of Asp^48 at the A-C border; the distal amide CO hydrogen bonds to the backbone NH of Arg^47; and the distal DFMP interacts with Lys^41 and Arg^47 in the C site. Estimated contributions to the overall ligand binding affinity for each substituent are also indicated.
Figure 5.
FIGURE 5. Crystal structure of PTP1B/5. The ortho-Cl substituent of the inhibitor binds in the D site where it participates in VDW interactions with Tyr^46, Ser^216, Asp^181, and Phe^182 and it is only 3.1 and 3.5 Å from one of the sulfone oxygens and the CH of the heterocycle, respectively. The IZD-phenyl template and aryl sulfonamide bind in previously observed conformations, and salicylate binds in the B site where it is in VDW contact with Met^258 and hydrogen bonds to Arg^24 and Arg^254. The linker that spans the A and B sites is well defined in the electron density even though it does not interact extensively with nonpolar residues.
The above figures are reprinted by permission from the ASBMB: J Biol Chem (2006, 281, 38013-38021) copyright 2006.
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