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Article

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

Supporting Info

Paolo Ruzza,*^‡ Luca Cesaro,^§ Dirk Tourwé, Andrea Calderan,^‡ Barbara Biondi,^‡ Veronique Maes, Ileana Menegazzo, Alessio Osler,^‡ Chiara Rubini,^‡ Andrea Guiotto,^‡ Lorenzo A. Pinna,^§ Gianfranco Borin,^†^‡ and Arianna Donella-Deana^§

Institute of Biomolecular Chemistry of CNR, Padova Unit, via F. Marzolo 1, 35131 Padova, Italy, Department of Biological Chemistry, University of Padova, via G. Colombo 3, 35131 Padova, Italy, Vrije Universiteit Brussel, Organic Chemistry Department, Pleinlann 2, B-1050 Brussel, Belgium, and Department of Chemical Sciences, University of Padova, via F. Marzolo 1, 35131 Padova, Italy

J. Med. Chem., 2006, 49 (6), pp 1916–1924

DOI: 10.1021/jm051080q

Publication Date (Web): February 16, 2006

†

Deceased November 21, 2005. This paper is dedicated to the memory of Dr. Gianfranco Borin, an outstanding and enthusiastic mentor, a dear friend and colleague.

To whom correspondence should be addressed. Phone: +390498275282. Fax: +390498275239. E-mail: paolo.ruzza@unipd.it.

‡

Institute of Biomolecular Chemistry of CNR.

Department of Biological Chemistry, University of Padova.

Vrije Universiteit Brussel.

Department of Chemical Sciences, University of Padova.

Abstract

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.

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