کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
9745074 | 1645297 | 2005 | 14 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Protein kinase structure and function analysis with chemical tools
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کلمات کلیدی
GRB2PKBPKGSREFMOCSH2tBuPTHRPKIPMPCSKMESNAPTKpSerCa2+/calmodulin kinase IIC-terminal Src kinasepTyrIRKPFACaMKIIAPPCATGSTtert-butylSHPPTPTOFPMA - LDC هاtris(2-carboxyethyl)phosphine - tris (2-carboxyethyl) فسفین2-mercaptoethanesulfonic acid - اسید 2-مروپتواتان سولفونیکExpressed protein ligation - اصلاح پروتئین بیان شدهCho - برایChinese Hamster Ovary - تخمدان هامستر چینیmatrix-assisted laser desorption/ionization - جذب / یونیزاسیون لیزر ماتریس کمک می کندtime of flight - زمان پروازTCEP - ساکتAANAT - عنانSerum response element - عنصر پاسخ سرمphosphothreonine - فسفاترونینphosphotyrosine - فسفاتیزینphosphoserine - فسفسئینfluorenylmethoxycarbonyl - فلورنیل متیل اکسید کربنیلMALDI - مالدیSrc Homology 2 - همبستگی Src 2Avian pancreatic polypeptide - پالپپتید پانکراس آواریProtein tyrosine phosphatase - پروتئین تیروزین فسفاتازProtein tyrosine kinase - پروتئین تیروزین کینازcGMP-dependent protein kinase - پروتئین کیناز وابسته به cGMPgrowth factor receptor-bound protein 2 - پروتئین گیرنده پروتئینی 2 عامل رشدchloramphenicol acetyltransferase - کلرامفنیکول استیل ترانسفرازInsulin receptor kinase - کیناز گیرنده انسولینglutathione S-transferase - گلوتاتیون S-ترانسفراز
موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آنالیزی یا شیمی تجزیه
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Protein kinases are the largest enzyme superfamily involved in cell signal transduction and represent therapeutic targets for a range of diseases. There have been intensive efforts from many labs to understand their catalytic mechanisms, discover inhibitors and discern their cellular functions. In this review, we will describe two approaches developed to analyze protein kinases: bisubstrate analog inhibition and phosphonate analog utilization. Both of these methods have been used in combination with the protein semisynthesis method expressed protein ligation to advance our understanding of kinase-substrate interactions and functional elucidation of phosphorylation. Previous work on the nature of the protein kinase mechanism suggests it follows a dissociative transition state. A bisubstrate analog was designed against the insulin receptor kinase to mimic the geometry of a dissociative transition state reaction coordinate distance. This bisubstrate compound proved to be a potent inhibitor against the insulin receptor kinase and occupied both peptide and nucleotide binding sites. Bisubstrate compounds with altered hydrogen bonding potential as well as varying spacers between the adenine and the peptide demonstrate the importance of the original design features. We have also shown that related bisubstrate analogs can be used to potently block serine/threonine kinases including protein kinase A. Since many protein kinases recognize folded protein substrates for efficient phosphorylation, it was advantageous to incorporate the peptide-ATP conjugates into protein structures. Using expressed protein ligation, a Src-ATP conjugate was produced and shown to be a high affinity ligand for the Csk tyrosine kinase. Nonhydrolyzable mimics of phosphoSer/phosphoTyr can be useful in examining the functionality of phosphorylation events. Using expressed protein ligation, we have employed phosphonomethylene phenylalanine and phosphonomethylene alanine to probe the phosphorylation of Tyr and Ser, respectively. These tools have permitted an analysis of the SH2-phosphatases (SHP1 and SHP2), revealing a novel intramolecular stimulation of catalytic activity mediated by the corresponding phosphorylation events. They have also been used to characterize the cellular regulation of the melatonin rhythm enzyme by phosphorylation.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics - Volume 1754, Issues 1â2, 30 December 2005, Pages 65-78
Journal: Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics - Volume 1754, Issues 1â2, 30 December 2005, Pages 65-78
نویسندگان
Kui Shen, Aliya C. Hines, Dirk Schwarzer, Kerry A. Pickin, Philip A. Cole,