JBC Avanti Polar Lipids

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J Biol Chem, Vol. 273, Issue 32, 20238-20242, August 7, 1998

Carboxymethyl-phenylalanine as a Replacement for Phosphotyrosine in SH2 Domain Binding

Liang Tong, Thomas C. Warren, Susan Lukas, Josephine Schembri-King, Raj Betageri, John R. Proudfoot, and Scott Jakes

From Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877

The crystal structure of human p56lck SH2 domain in complex with an inhibitor containing the singly charged p-(carboxymethyl)phenylalanine residue (cmF) as a phosphotyrosine (Tyr(P) or pY) replacement has been determined at 1.8 Å resolution. The binding mode of the acetyl-cmF-Glu-Glu-Ile (cmFEEI) inhibitor is very similar to that of the pYEEI inhibitor, confirming that the cmFEEI inhibitor has a similar mechanism of SH2 domain inhibition despite its significantly reduced potency. Observed conformational differences in the side chain of the cmF residue can be interpreted in terms of maintaining similar interactions with the SH2 domain as the Tyr(P) residue. The crystal structure of the free p56lck SH2 domain has been determined at 1.9 Å resolution and shows an open conformation for the BC loop and an open phosphotyrosine binding pocket, in contrast to earlier studies on the src SH2 domain that showed mostly closed conformation. The structural information presented here suggests that the carboxymethyl-phenylalanine residue may be a viable Tyr(P) replacement and represents an attractive starting point for the design and development of SH2 domain inhibitors with better pharmaceutical profiles.

Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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