2CMC

Structural Basis for Inhibition of Protein Tyrosine Phosphatase 1B by Isothiazolidinone Heterocyclic Phosphonate Mimetics

Summary for 2CMC

• Entry DOI: 10.2210/pdb2cmc/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 2CNE 2CNF 2CNG 2CNH 2CNI 2F6F 2F6T 2F6V 2F6W 2F6Y 2F6Z 2F70 2F71 2FJM 2FJN 2HNP 2HNQ
• Descriptor: TYROSINE-PROTEIN PHOSPHATASE NON-RECEPTOR TYPE 1, N-ACETYL-L-PHENYLALANYL-4-[DIFLUORO(PHOSPHONO)METHYL]-L-PHENYLALANINAMIDE, SULFATE ION, ... (5 entities in total)
• Functional Keywords: polymorphism, phosphorylation, protein phosphatase, endoplasmic reticulum, oxidation, hydrolase, acetylation, phosphatase
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 36421.28

Authors

Ala, P.J.,Gonneville, L.,Hillman, M.C.,Becker-Pasha, M.,Wei, M.,Reid, B.G.,Klabe, R.,Yue, E.W.,Wayland, B.,Douty, B.,Combs, A.P.,Polam, P.,Wasserman, Z.,Bower, M.,Burn, T.C.,Hollis, G.F.,Wynn, R. (deposition date: 2006-05-04, release date: 2006-08-17, Last modification date: 2024-05-08)

Primary citation

Ala, P.J.,Gonneville, L.,Hillman, M.C.,Becker-Pasha, M.,Wei, M.,Reid, B.G.,Klabe, R.,Yue, E.W.,Wayland, B.,Douty, B.,Polam, P.,Wasserman, Z.,Bower, M.,Combs, A.P.,Burn, T.C.,Hollis, G.F.,Wynn, R.
Structural Basis for Inhibition of Protein-Tyrosine Phosphatase 1B by Isothiazolidinone Heterocyclic Phosphonate Mimetics.
J.Biol.Chem., 281:32784-, 2006

PubMed 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.

PubMed: 16916797
DOI: 10.1074/JBC.M606873200

Experimental method

X-RAY DIFFRACTION (2.2 Å)