High resolution crystal structure of the Grb2 SH2 domain with a phosphopeptide derived from CD28.

Src homology 2 (SH2) domains play a critical role in cellular signal transduction. They bind to peptides containing phosphotyrosine (pY) with various specificities that depend on the flanking amino-acid residues. The SH2 domain of growth-factor receptor-bound protein 2 (Grb2) specifically recognizes pY-X-N-X, whereas the SH2 domains in phosphatidylinositol 3-kinase (PI3K) recognize pY-X-X-M. Binding of the pY site in CD28 (pY-M-N-M) by PI3K and Grb2 through their SH2 domains is a key step that triggers the CD28 signal transduction for T cell activation and differentiation. In this study, we determined the crystal structure of the Grb2 SH2 domain in complex with a pY-containing peptide derived from CD28 at 1.35 Å resolution. The peptide was found to adopt a twisted U-type conformation, similar to, but distinct from type-I β-turn. In all previously reported crystal structures, the peptide bound to the Grb2 SH2 domains adopts a type-I β-turn conformation, except those with a proline residue at the pY+3 position. Molecular modeling also suggests that the same peptide bound to PI3K might adopt a very different conformation

Statistics for data collection and structure refinement.

*<p>Values shown in parentheses are for the highest-resolution shell.</p

A model structure of the CD28-derived peptide bound to PI3K N.

<p>(A) The crystal structure of the amino-terminal SH2 domain of PI3K (PI3K N SH2) with a phosphopeptide derived from c-Kit (T-N-E-pY-M-D-M-K) and (B) a molecular model of PI3K N SH2 with the CD28-derived peptide (S-D-pY-M-N-M-T). The SH2 domains are shown as surface models, whereas the phosphopeptides are shown as stick models.</p

前立腺癌IMRTの初期治療成績

Purpose : We started curative irradiation using intensity-modulated radiation therapy (IMRT) for prostate cancer from 2010. Forty eight patients who underwent IMRT at a total dose of 74Gy/37Fr were examined retrospectively for their efficacy and safety. / Materials and methods : Forty eight patients who underwent 74Gy/37Fr IMRT at our hospital from July 2012 to July 2014 were retrospectively examined. The details of patients were as below. T factor : T1/T2/T3/T4=25/15/7/1, Risk classification (NCCN) : low/intermediate/high/locally advanced very high=5/27/11/5, Age : 53 to 84 years old (median 73), Prostate specific antigen (PSA) before IMRT : under0.008 to 42.687 (median 6.450), Hormonal therapy : with/without =14/34. The observation period was 1.7 to 39 months (median 24.4). The treatment method was fixed 7 fields of IMRT for 45 cases, volumetric modulated arc therapy (VMAT) for 3 cases. In principle, planning target volume (PTV) mean prescription was used for planning. We examined for clinical/biochemical recurrence, and acute/late adverse events (CTCAE ver. 4.0) retrospectively. / Results : No primary disease death was occurred. No clinical recurrence was observed, but biochemical recurrence was detected in one (2.1％). Adverse events as acute phase injuries, Grade 1-2 of frequent urination in 35 (72.9％), miction pain in 7 (14.6％), and Grade 2 of dysuria in one (2.1％) were observed. Grade 1 of rectal bleeding was appeared in 2 (4.2％) as late adverse events. No serious acute and late adverse effects (≧Grade 3) were occurred. / Conclusion : Our clinical results of 74Gy/37Fr IMRT showed favorable efficacy and safety compared with past reports, however the observation period was rather short. Based on this results, IMRT is currently performed with the increased total dose of 78Gy/39Fr for intermediate and high risk prostate cancer.はじめに / 目的 / 対象と方法 / 対象 / 方法 / 結果 / 考察 / 結論 / 参考文