期刊
ACS CHEMICAL BIOLOGY
卷 4, 期 5, 页码 325-334出版社
AMER CHEMICAL SOC
DOI: 10.1021/cb800314v
关键词
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资金
- National Institutes of Health [R01-GM72688, U54-GM74946, R21-CA132700, R21-DA025725]
- NATIONAL CANCER INSTITUTE [R21CA132700] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM072688, U54GM074946] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R21DA025725] Funding Source: NIH RePORTER
Combinatorial libraries built with severely restricted chemical diversity have yielded highly functional synthetic binding proteins. Structural analyses of these minimalist binding sites have revealed the dominant role of large tyrosine residues for mediating molecular contacts and of small serine/glycine residues for providing space and flexibility. The concept of using limited residue types to construct optimized binding proteins mirrors findings in the field of small molecule drug development, where it has been proposed that most drugs are built from a limited set of side chains presented by diverse frameworks. The physicochemical properties of tyrosine make it the amino acid that is most effective for mediating molecular recognition, and protein engineers have taken advantage of these characteristics to build tyrosine-rich protein binding sites that outperform natural proteins in terms of affinity and specificity. Knowledge from preceding studies can be used to improve current designs, and thus synthetic protein libraries will continue to evolve and improve. In the near future, it seems likely that synthetic binding proteins will supersede natural antibodies for most purposes, and moreover, synthetic proteins will enable many new applications beyond the scope of natural proteins.
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