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Monobodies are synthetic binding proteins that are constructed using a fibronectin type III domain (FN3) as a molecular scaffold. Monobodies are simple and robust alternative to antibodies for creating target-binding proteins. The term "monobody" was coined in 1998 by the Koide group who published the first paper demonstrating the monobody concept using the tenth FN3 domain of human fibronectin. Monobodies are generated from combinatorial libraries in which portions of the FN3 scaffold are diversified using molecular display and directed evolution technologies such as phage display, mRNA display and yeast surface display.〔(), Koide S, Koide A, Lipovšek D (2012). Target-binding proteins based on the 10th human fibronectin type III domain (¹⁰Fn3). Methods Enzymol. 503:135-56.〕〔(), Koide A, Wojcik J, Gilbreth RN, Hoey RJ, Koide S (2012). Teaching an old scaffold new tricks: monobodies constructed using alternative surfaces of the FN3 scaffold. J Mol Biol. 415:393-405.〕 A large number of monobodies that have high affinity and high specificity to their respective targets have been reported.〔(), Wojcik J, Hantschel O, Grebien F, Kaupe I, Bennett KL, Barkinge J, Jones RB, Koide A, Superti-Furga G, Koide S (2010). A potent and highly specific FN3 monobody inhibitor of the Abl SH2 domain. Nat Struct Mol Biol. 17:519-27.〕〔(), Gilbreth RN, Truong K, Madu I, Koide A, Wojcik JB, Li NS, Piccirilli JA, Chen Y, Koide S (2011). Isoform-specific monobody inhibitors of small ubiquitin-related modifiers engineered using structure-guided library design. Proc Natl Acad Sci U S A. 108:7751-6.〕〔(), Grebien F, Hantschel O, Wojcik J, Kaupe I, Kovacic B, Wyrzucki AM, Gish GD,Cerny-Reiterer S, Koide A, Beug H, Pawson T, Valent P, Koide S, Superti-Furga G (2011). Targeting the SH2-kinase interface in Bcr-Abl inhibits leukemogenesis. Cell 147:306-19.〕〔(), Sha F, Gencer EB, Georgeon S, Koide A, Yasui N, Koide S, Hantschel O (2013). Dissection of the BCR-ABL signaling network using highly specific monobody inhibitors to the SHP2 SH2 domains. Proc Natl Acad Sci U S A. 110:14924-9.〕〔(), Stockbridge RB, Koide A, Miller C, Koide S (2014). Proof of dual-topology architecture of Fluc F- channels with monobody blockers. Nat Commun 5:5120.〕 Monobodies belong to the class of molecules collectively called antibody mimics (or Antibody mimetics) and alternative scaffolds that aim to overcome shortcomings of natural antibody molecules. A major advantage of monobodies over conventional antibodies is that monobodies can readily be used as genetically encoded intracellular inhibitors, that is you can express a monobody inhibitor in a cell of choice by simply transfecting the cell with a monobody expression vector.〔(), Grebien F, Hantschel O, Wojcik J, Kaupe I, Kovacic B, Wyrzucki AM, Gish GD,Cerny-Reiterer S, Koide A, Beug H, Pawson T, Valent P, Koide S, Superti-Furga G (2011). Targeting the SH2-kinase interface in Bcr-Abl inhibits leukemogenesis. Cell 147:306-19.〕〔(), Sha F, Gencer EB, Georgeon S, Koide A, Yasui N, Koide S, Hantschel O (2013). Dissection of the BCR-ABL signaling network using highly specific monobody inhibitors to the SHP2 SH2 domains. Proc Natl Acad Sci U S A. 110:14924-9.〕 This is because of unique characteristics of the underlying FN3 scaffold: small (~90 residues), stable, easy to produce, and its lack of disulfide bonds that makes it possible to produce functional monobodies regardless of the redox potential of the cellular environment, including the reducing environment of the cytoplasm and nucleus. In contrast, most antibodies and antibody fragments dependend on disulfide bonds formation and they must be produced under an oxidizing environment. The monobody technology has been adopted in the biotechnology industry, most notably by Adnexus, a biotechnology company which has been part of Bristol-Myers Squibb since 2007 under the name of Adnectins (originally as Trinectins by its predecesor, Phylos〔http://www.ncbi.nlm.nih.gov/pubmed/12204693〕). An example is pegdinetanib (Angiocept), an antagonist of vascular endothelial growth factor receptor 2 (VEGFR-2), which has entered Phase II clinical trials investigating the treatment of glioblastoma in October 2007. ==Structure== The wild-type FN3 scaffold, consists of 94 amino acids and has a molecular mass of about 10 kDa, fifteen times smaller than an IgG type antibody and comparable the size of a single variable domain of an antibody. They are based on the structure of human fibronectin, more specifically on its tenth extracellular type III domain. This domain has a structure similar to antibody variable domains, with seven beta sheets forming a beta-sandwich and three exposed loops on each side corresponding to the three complementarity determining regions. Monobodies lack binding sites for metal ions and the central disulfide bond. Monobodies with specificity for different proteins can be tailored by modifying the loops BC (between the second and third beta sheets) and FG (between the sixth and seventh sheets). 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「monobody」の詳細全文を読む スポンサード リンク
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