2CNH
Structural Insights into the Design of Nonpeptidic Isothiazolidinone- Containing Inhibitors of Protein Tyrosine Phosphatase 1B
Summary for 2CNH
| Entry DOI | 10.2210/pdb2cnh/pdb |
| Related | 1A5Y 1AAX 1BZC 1BZH 1BZJ 1C83 1C84 1C85 1C86 1C87 1C88 1ECV 1EEN 1EEO 1G1F 1G1G 1G1H 1G7F 1G7G 1GFY 1I57 1JF7 1KAK 1KAV 1L8G 1LQF 1NL9 1NNY 1NO6 1NWE 1NWL 1NZ7 1OEM 1OEO 1OES 1OET 1OEU 1OEV 1ONY 1ONZ 1PA1 1PH0 1PTT 1PTU 1PTV 1PTY 1PXH 1PYN 1Q1M 1Q6J 1Q6M 1Q6N 1Q6P 1Q6S 1Q6T 1QXK 1SUG 1T48 1T49 1T4J 1WAX 1XBO 2AZR 2B07 2B4S 2BGD 2BGE 2CM2 2CM3 2CM7 2CM8 2CMA 2CMB 2CMC 2CNE 2CNF 2CNG 2CNI 2F6F 2F6T 2F6V 2F6W 2F6Y 2F6Z 2F70 2F71 2FJM 2FJN 2HNP 2HNQ |
| Descriptor | TYROSINE-PROTEIN PHOSPHATASE NON-RECEPTOR TYPE 1, CALCIUM ION, N-[(1S)-1-(1H-BENZIMIDAZOL-2-YL)-2-{4-[(5S)-1,1-DIOXIDO-3-OXOISOTHIAZOLIDIN-5-YL]PHENYL}ETHYL]-4-METHYL-3,4-DIHYDRO-2H-1,4-BENZOXAZINE-7-SULFONAMIDE, ... (4 entities in total) |
| Functional Keywords | polymorphism, phosphorylation, protein phosphatase, endoplasmic reticulum, oxidation, hydrolase, acetylation, phosphatase |
| Biological source | HOMO SAPIENS (HUMAN) |
| Cellular location | Endoplasmic reticulum membrane ; Peripheral membrane protein ; Cytoplasmic side : P18031 |
| Total number of polymer chains | 1 |
| Total formula weight | 37987.38 |
| Authors | Ala, P.J.,Gonneville, L.,Hillman, M.,Becker-Pasha, M.,Yue, E.W.,Douty, B.,Wayland, B.,Polam, P.,Crawley, M.L.,McLaughlin, E.,Sparks, R.B.,Glass, B.,Takvorian, A.,Combs, A.P.,Burn, T.C.,Hollis, G.F.,Wynn, R. (deposition date: 2006-05-21, release date: 2006-09-27, Last modification date: 2023-12-13) |
| Primary citation | Ala, P.J.,Gonneville, L.,Hillman, M.,Becker-Pasha, M.,Yue, E.W.,Douty, B.,Wayland, B.,Polam, P.,Crawley, M.L.,Mclaughlin, E.,Sparks, R.B.,Glass, B.,Takvorian, A.,Combs, A.P.,Burn, T.C.,Hollis, G.F.,Wynn, R. Structural Insights Into the Design of Nonpeptidic Isothiazolidinone-Containing Inhibitors of Protein- Tyrosine Phosphatase 1B. J.Biol.Chem., 281:38013-, 2006 Cited by PubMed 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. PubMed: 17028182DOI: 10.1074/JBC.M607913200 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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