Synthesis and structure activity studies of phosphatase resistant SH2 domain inhibiting peptides: D-amino acid effects

Phospholipase C-gamma (PLC-gamma) is a substrate of the fibroblast growth factor receptor (FGFR; encoded by the flg gene) and other receptors with tyrosine kinase activity. It has been demonstrated that the src homology region 2 (SH2 domain) of PLC-gamma and of other signalling molecules such as GTPase-activating protein and phosphatidylinositol 3-kinase-associated p85 direct their binding toward tyrosine-autophosphorylated regions of the epidermal growth factor or platelet-derived growth factor receptor. In this report, we describe the identification of Tyr-766 as an autophosphorylation site of flg-encoded FGFR by direct sequencing of a tyrosine-phosphorylated tryptic peptide isolated from the cytoplasmic domain of FGFR expressed in Escherichia coli. The same phosphopeptide was found in wild-type FGFR phosphorylated either in vitro or in living cells. Like other growth factor receptors, tyrosine-phosphorylated wild-type FGFR or its cytoplasmic domain becomes associated with intact PLC-gamma or with a fusion protein containing the SH2 domain of PLC-gamma. To delineate the site of association, we have examined the capacity of a 28-amino-acid tryptic peptide containing phosphorylated Tyr-766 to bind to various constructs containing SH2 and other domains of PLC-gamma. It is demonstrated that the tyrosine-phosphorylated peptide binds specifically to the SH2 domain but not to the SH3 domain or other regions of PLC-gamma. Hence, Tyr-766 and its flanking sequences represent a major binding site in FGFR for PLC-gamma. Alignment of the amino acid sequences surrounding Tyr-766 with corresponding regions of other FGFRs revealed conserved tyrosine residues in all known members of the FGFR family. We propose that homologous tyrosine-phosphorylated regions in other FGFRs also function as binding sites for PLC-gamma and therefore are involved in coupling to phosphatidylinositol breakdown.

Download Full-text

Identification and Structure–Activity Relationship Study of Imidazo[1,2-a]pyridine-3-amines as First Selective Inhibitors of Excitatory Amino Acid Transporter Subtype 3 (EAAT3)

ACS Chemical Neuroscience ◽

10.1021/acschemneuro.9b00447 ◽

2019 ◽

Vol 10 (10) ◽

pp. 4414-4429

Author(s):

Peng Wu ◽

Walden E. Bjørn-Yoshimoto ◽

Markus Staudt ◽

Anders A. Jensen ◽

Lennart Bunch

Keyword(s):

Amino Acid ◽

Excitatory Amino Acid ◽

Structure Activity Relationship ◽

Amino Acid Transporter ◽

Activity Relationship ◽

Selective Inhibitors ◽

Excitatory Amino Acid Transporter ◽

Structure Activity ◽

Relationship Study ◽

Subtype 3

Download Full-text

Structure-Activity Studies on the Abl-SH2 Domain

American Peptide Symposia - Peptides Frontiers of Peptide Science ◽

10.1007/0-306-46862-x_199 ◽

2005 ◽

pp. 459-460

Author(s):

Maria Pietanza ◽

Tom Muir

Keyword(s):

Sh2 Domain ◽

Structure Activity

Download Full-text

Quantitative Structure−Activity Relationship Modeling of Peptide and Protein Behavior as a Function of Amino Acid Composition

Journal of Agricultural and Food Chemistry ◽

10.1021/jf000718y ◽

2001 ◽

Vol 49 (2) ◽

pp. 851-858 ◽

Cited By ~ 18

Author(s):

Karl J. Siebert

Keyword(s):

Amino Acid ◽

Amino Acid Composition ◽

Acid Composition ◽

Quantitative Structure Activity Relationship ◽

Structure Activity Relationship ◽

Activity Relationship ◽

Quantitative Structure ◽

Structure Activity

Download Full-text

The anti-leishmanial activity of dipeptide esters on Leishmania amazonensis amastigotes

Parasitology ◽

10.1017/s0031182000061205 ◽

1990 ◽

Vol 100 (2) ◽

pp. 201-207 ◽

Cited By ~ 6

Author(s):

C. Ramazeilles ◽

L. Juliano ◽

J. R. Chagas ◽

M. Rabinovitch

Keyword(s):

Amino Acid ◽

Methyl Esters ◽

Leishmania Amazonensis ◽

Amino Acid Esters ◽

Cysteine Proteinases ◽

Hydrophobic Amino Acid ◽

Structure Activity ◽

Reduction Assay ◽

Mtt Reduction ◽

Acid Esters

SUMMARYL-Amino acid esters, such as L-Leu-OMe, kill Leishmania amazonensis amastigotes by a mechanism which appears to involve ester hydrolysis by cysteine proteinases located in the parasite megasomes. We have examined the killing of isolated amastigotes by L-dipeptide esters and derived some structure-activity correlations. Toxicity of the compounds for the parasites was measured by a tetrazolium (MTT) reduction assay. The results show that active dipeptide esters contained at least I hydrophobic amino acid (Leu, Ile, Val, Phe or Trp). The activity of homodipeptide methyl esters depended on the nature of the amino acid, as indicated by the following series: Phe-Phe-OMe < Val-Val-OMe < Leu-Leu-OMe < Trp-Trp-OMe < Ile-Ile-OMe. The nature of the amino acids in Leu-X-OMe and X-Leu-OMe was relatively unimportant when X was Phe, Trp or Val. However, when X was Ala or Gly, Leu-X-OMe was several-fold more active than X-Leu-OMe.

Download Full-text