Tong L, Warren T C, Lukas S, Schembri-King J, Betageri R, Proudfoot J R, Jakes S
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877, USA.
J Biol Chem. 1998 Aug 7;273(32):20238-42. doi: 10.1074/jbc.273.32.20238.
The crystal structure of human p56(lck) 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 A 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 p56(lck) SH2 domain has been determined at 1.9 A 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.
已确定人p56(lck) SH2结构域与一种含有单电荷对（羧甲基）苯丙氨酸残基（cmF）作为磷酸酪氨酸（Tyr(P)或pY）替代物的抑制剂形成复合物时的晶体结构，分辨率为1.8埃。乙酰基-cmF-谷氨酸-谷氨酸-异亮氨酸（cmFEEI）抑制剂的结合模式与pYEEI抑制剂非常相似，这证实了cmFEEI抑制剂尽管效力显著降低，但具有类似的SH2结构域抑制机制。cmF残基侧链中观察到的构象差异可以通过与SH2结构域保持与Tyr(P)残基相似的相互作用来解释。游离p56(lck) SH2结构域的晶体结构已确定，分辨率为1.9埃，显示BC环呈开放构象，磷酸酪氨酸结合口袋开放，这与早期对src SH2结构域的研究结果相反，早期研究大多显示其为封闭构象。此处提供的结构信息表明，羧甲基苯丙氨酸残基可能是一种可行的Tyr(P)替代物，是设计和开发具有更好药物特性的SH2结构域抑制剂的一个有吸引力的起点。
