Conformational constraints of tyrosine in protein tyrosine kinase substrates: Information about preferred bioactive side-chain orientation

✍ Scribed by Paolo Ruzza; Andrea Calderan; Arianna Donella-Deana; Barbara Biondi; Luca Cesaro; Alessio Osler; Stefano Elardo; Andrea Guiotto; Lorenzo A. Pinna; Gianfranco Borin

• Publisher: Wiley (John Wiley & Sons)
• Year: 2003
• Tongue: English
• Weight: 139 KB
• Volume: 71
• Category: Article
• ISSN: 0006-3525
• DOI: 10.1002/bip.10469

✦ Synopsis

Abstract

The side‐chain orientation of a tyrosine residue located in a peptide, which is an excellent substrate of Syk tyrosine kinase (A. M. Brunati, A. Donella‐Deana, M. Ruzzene, O. Marin, L. A. Pinna, FEBS Letters, 1995, Vol. 367, pp. 149–152), was fixed in the gauche (+) or gauche (−) conformation by using the 7‐hydroxy‐1,2,3,4‐tetrahydro isoquinoline‐3‐carboxylic (Htc) structure. The tyrosine trans conformation was blocked by using an aminobenzazepine‐type (Hba) structure. The proposed side‐chain orientations were confirmed by the analysis of the ^1^H‐NMR parameters: chemical shifts, coupling constants, and nuclear Overhauser effects to the tyrosine constraints in the different analogs. This “rotamer scan” of the phosphorylatable residue allowed us to generate optimal substrates in terms of both phosphorylation efficiency and selectivity for Syk tyrosine kinase. In contrast, these conformationally restricted tyrosine analogs were not tolerated by the Src‐related tyrosine kinases Lyn and c‐Fgr. © 2003 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 71: 478–488, 2003