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Conformational constraints of tyrosine in protein tyrosine kinase substrates: Information about preferred bioactive side‐chain orientation
Author(s) -
Ruzza Paolo,
Calderan Andrea,
DonellaDeana Arianna,
Biondi Barbara,
Cesaro Luca,
Osler Alessio,
Elardo Stefano,
Guiotto Andrea,
Pinna Lorenzo A.,
Borin Gianfranco
Publication year - 2003
Publication title -
peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.10469
Subject(s) - chemistry , tyrosine , side chain , sh2 domain , proto oncogene tyrosine protein kinase src , residue (chemistry) , stereochemistry , tyrosine kinase , tyrosine phosphorylation , receptor tyrosine kinase , selectivity , phosphorylation , biochemistry , signal transduction , organic chemistry , polymer , catalysis
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