Spatial Conformation and Topography of the Tyrosine Aromatic Ring in Substrate Recognition by Protein Tyrosine Kinases

• Published in: Journal of medicinal chemistry Vol. 49; no. 6; pp. 1916 - 1924
• Main Authors: Ruzza, Paolo, Cesaro, Luca, Tourwé, Dirk, Calderan, Andrea, Biondi, Barbara, Maes, Veronique, Menegazzo, Ileana, Osler, Alessio, Rubini, Chiara, Guiotto, Andrea, Pinna, Lorenzo A, Borin, Gianfranco, Donella-Deana, Arianna
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 23.03.2006; Amer Chemical Soc
• Subjects: Analytical, structural and metabolic biochemistry; Biological and medical sciences; Chemistry, Medicinal; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Kinetics; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Medical sciences; Miscellaneous; Models, Molecular; Molecular Conformation; Molecular Mimicry; Oligopeptides - chemical synthesis; Oligopeptides - chemistry; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Phosphorylation; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - chemistry; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Substrate Specificity; Transferases; Tyrosine - chemistry; ACTIVATION; DESIGN; PEPTIDES; SPECIFICITY; PHOSPHORYLATION; ANALOGS; ACIDS; SPIN COUPLING-CONSTANTS; CONSTRAINTS; PRACTICAL ASPECTS; Phosphorylation; Peptides; Enzyme; Transferases; Benzene derivatives; Selectivity; In vitro; Modeling; Substrate; Signal transduction; Octapeptide; Structure activity relation; Molecular model; Bicyclic compound; Aromatic compound; Catalytic site; Peptide synthesis; Kinetics; Chemical synthesis; Protein-tyrosine kinase; Conformation
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm051080q

The side chain orientation of the tyrosine residue included in a peptide, which is an excellent substrate of Syk tyrosine kinase, was fixed in different conformations by either incorporating the tyrosine in cyclic structures (6-OH-Tic, 5-OH-Aic, and Hat derivatives) or adding a sterically bulky substituent in the tyrosine side chain moiety (β-MeTyr). Synthetic peptides containing tyrosine analogues displaying different side chain orientations were analyzed by NMR techniques and tested as potential substrates of the nonreceptor tyrosine kinases Syk, Csk, Lyn, and Fyn. The “rotamer scan” of the phosphorylatable residue generated optimal substrates in terms of both phosphorylation efficiency and selectivity for Syk tyrosine kinase, while the peptidomimetics were not recognized by the other tyrosine kinases. In particular, l-β-MeTyr and d-Hat containing peptides resulted to be both suitable substrates for the specific monitoring of Syk and consensus sequence scaffolds for the design of potential inhibitors highly selective for this tyrosine kinase.