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Stat3 (signal transducer and activator of transcription) is constitutively active in several cancer types and is a target for anti-cancer drug design. Compounds targeted to the SH2 domain would uncouple this protein from its roles in the aberrant survival and cell cycling pathways that characterize cancer cells. The design of peptidominetics targeted to Stat3 would be greatly aided by a model of phosphopeptides bound to the SH2 domain. The SH2 domains of four STAT proteins crystallized to date show remarkably high tertiary structure overlap. In comparison to the SH2 domains of non-STAT proteins such as Grb-family adapters, p85PI3K, Src-family kinases, etc, the STATs have sequence deletions in the EF loop region. Instead, they have a pocket that resides between beta strand D and a unique helix. We used the X-ray structure of the complex of Stat1 and Ac-pTyr-Asp-Lys-Pro-His [1] as a template to propose a model of interactions between pTyr-Xxx-Xxx-Gln peptides and Stat3. Ac-pTyr-Leu-Pro-Gln-NHBn [2] was docked into the SH2 domain of Stat3 using InsightII and the assembly was subjected to energy minimization. In addition to the “standard” phosphotyrosine interactions, the complex reveals peptide backbone-protein hydrogen bonds between Leu NH and C=O, Pro C=O and the NH of the benzyl amide that are in keeping with results of structure-activity studies published previously [2]. These interactions are unique to STAT-peptide interactions. The CONH2 of Gln resides in a pocket between beta strand D and the unique helix and can form hydrogen bonds with the main chain carbonyl groups of Pro639 and Tyr640. Beta-substituted Gln analogues bind poorly supporting a tight interaction in the proposed pocket. The model proposed in this study has potential use in the design of peptidomimetic inhibitors of Stat3.

1. Mao et al Mol. Cell 17:761-71, 2005

2. Coleman et al. J.Med. Chem. 48:6661, 2005

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA