Stabilization of Charges and Protonation States in the Active Site of the Protein Tyrosine Phosphatases:  A Computational Study†

2000 ◽  
Vol 104 (47) ◽  
pp. 11321-11333 ◽  
Author(s):  
Valérie Dillet ◽  
Robert L. Van Etten ◽  
Donald Bashford
Keyword(s):  
Active Site ◽  
Computational Study ◽  
Protein Tyrosine Phosphatases ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine

scholarly journals [Difluro(phosphono)methyl]phenylalanine-containing peptide inhibitors of protein tyrosine phosphatases

1999 ◽  
Vol 337 (2) ◽  
pp. 219-223 ◽  
Author(s):  
Sylvie DESMARAIS ◽  
Richard W. FRIESEN ◽  
Robert ZAMBONI ◽  
Chidambaram RAMACHANDRAN
Keyword(s):  
Active Site ◽  
Protein Tyrosine Phosphatases ◽  
Selective Inhibitor ◽  
Peptide Inhibitors ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine

Peptides containing the non-hydrolysable phosphotyrosine analogue 4-[difluro(phosphono)methyl]phenylalanine [Phe(CF2P)] were synthesized and tested as inhibitors of the protein tyrosine phosphatases (PTPs) PTP1B, CD45, PTPβ, LAR and SHP-1. We have identified peptides containing two adjacent Phe(CF2P) residues as potent inhibitors of PTPs. The tripeptide having the sequence Glu-Phe(CF2P)-Phe(CF2P) is a potent and selective inhibitor of PTP1B. This peptide inhibits PTP1B with an IC50 of 40 nM, which is at least 100-fold lower than with other PTPs. A second tripeptide, Pro-Phe(CF2P)-Phe(CF2P), is most potent against PTPβ, with an IC50 of 200 nM, and inhibits PTP1B with an IC50 of 300 nM. These data suggest that it is possible to develop selective, active-site-directed, reversible, potent inhibitors of PTPs.

scholarly journals Conformational Motions Regulate Phosphoryl Transfer in Related Protein Tyrosine Phosphatases

Science ◽  
2013 ◽  
Vol 341 (6148) ◽  
pp. 899-903 ◽  
Author(s):  
Sean K. Whittier ◽  
Alvan C. Hengge ◽  
J. Patrick Loria
Keyword(s):  
Active Site ◽  
Protein Tyrosine Phosphatases ◽  
Binding Pocket ◽  
Resonance Spectroscopy ◽  
Phosphoryl Transfer ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine ◽  
Leaving Group ◽  
Kinetics Of ◽  
Loop Motion

Many studies have implicated a role for conformational motions during the catalytic cycle, acting to optimize the binding pocket or facilitate product release, but a more intimate role in the chemical reaction has not been described. We address this by monitoring active-site loop motion in two protein tyrosine phosphatases (PTPs) using nuclear magnetic resonance spectroscopy. The PTPs, YopH and PTP1B, have very different catalytic rates; however, we find in both that the active-site loop closes to its catalytically competent position at rates that mirror the phosphotyrosine cleavage kinetics. This loop contains the catalytic acid, suggesting that loop closure occurs concomitantly with the protonation of the leaving group tyrosine and explains the different kinetics of two otherwise chemically and mechanistically indistinguishable enzymes.

scholarly journals Suramin Is an Active Site-directed, Reversible, and Tight-binding Inhibitor of Protein-tyrosine Phosphatases

1998 ◽  
Vol 273 (20) ◽  
pp. 12281-12287 ◽  
Author(s):  
Yan-Ling Zhang ◽  
Yen-Fang Keng ◽  
Yu Zhao ◽  
Li Wu ◽  
Zhong-Yin Zhang
Keyword(s):  
Active Site ◽  
Tight Binding ◽  
Protein Tyrosine Phosphatases ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine

Thiophosphorylated Substrate Analogs Are Potent Active Site-Directed Inhibitors of Protein-Tyrosine Phosphatases

1994 ◽  
Vol 223 (1) ◽  
pp. 51-58 ◽  
Author(s):  
K.T. Hiriyanna ◽  
D. Baedke ◽  
K.H. Baek ◽  
B.A. Forney ◽  
G. Kordiyak ◽  
...  
Keyword(s):  
Active Site ◽  
Protein Tyrosine Phosphatases ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine ◽  
Substrate Analogs

scholarly journals Structural Insights into the Active Site Formation of DUSP22 in N-loop-containing Protein Tyrosine Phosphatases

2020 ◽  
Vol 21 (20) ◽  
pp. 7515
Author(s):  
Chih-Hsuan Lai ◽  
Co-Chih Chang ◽  
Huai-Chia Chuang ◽  
Tse-Hua Tan ◽  
Ping-Chiang Lyu
Keyword(s):  
Hydrogen Bonding ◽  
Phosphatase Activity ◽  
Conformational Changes ◽  
Active Site ◽  
Protein Tyrosine Phosphatases ◽  
Site Formation ◽  
Tyrosine Phosphatases ◽  
Conserved Residues ◽  
Protein Tyrosine ◽  
Hydrogen Bonding Network

Cysteine-based protein tyrosine phosphatases (Cys-based PTPs) perform dephosphorylation to regulate signaling pathways in cellular responses. The hydrogen bonding network in their active site plays an important conformational role and supports the phosphatase activity. Nearly half of dual-specificity phosphatases (DUSPs) use three conserved residues, including aspartate in the D-loop, serine in the P-loop, and asparagine in the N-loop, to form the hydrogen bonding network, the D-, P-, N-triloop interaction (DPN–triloop interaction). In this study, DUSP22 is used to investigate the importance of the DPN–triloop interaction in active site formation. Alanine mutations and somatic mutations of the conserved residues, D57, S93, and N128 substantially decrease catalytic efficiency (kcat/KM) by more than 102-fold. Structural studies by NMR and crystallography reveal that each residue can perturb the three loops and induce conformational changes, indicating that the hydrogen bonding network aligns the residues in the correct positions for substrate interaction and catalysis. Studying the DPN–triloop interaction reveals the mechanism maintaining phosphatase activity in N-loop-containing PTPs and provides a foundation for further investigation of active site formation in different members of this protein class.

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