Structure-Based Design of a Novel Series of Nonpeptide Ligands That Bind to the pp60src SH2 Domain

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• 作者：Elizabeth A. Lunney ; Kimberly S. Para ; J. Ronald Rubin ; Christine Humblet ; James H. Fergus ; James S. Marks ; and Tomi K. Sawyer
• 刊名：Journal of the American Chemical Society
• 出版年：1997
• 出版时间：December 24, 1997
• 年：1997
• 卷：119
• 期：51
• 页码：12471 - 12476
• 全文大小：586K
• 年卷期：v.119,no.51(December 24, 1997)
• ISSN：1520-5126

文摘

The SH2 domain of pp60^c-src (Src), a nonreceptortyrosine kinase, facilitates signal transduction in anumber of cell types through binding to cognate phosphorylated proteinsequences. Phosphotyrosine-containingpeptides have been shown to bind to the Src SH2 domain with micromolaraffinity. Guided by the X-ray crystalstructure of a phosphorylated peptide bound to the Src SH2 domain, wehave designed a de novo series of smallmolecule ligands that bind with affinity comparable to the parentphosphopeptide. An X-ray crystal structure of theSrc SH2 domain bound with a nonpeptide analog from this series verifiesinteractions targeted in the moleculardesign. However, a unique mode of binding has been revealed forthe P-site phenyl phosphate group of the nonpeptidethat differs from that observed for the phosphotyrosine side chain inpeptide ligands bound to the Src SH2 domain.This novel binding mode is being used in guiding future designefforts.