Genetically Encoding an Electrophilic Amino Acid for Protein Stapling and Covalent Binding to Native Receptors

Covalent bonds can be generated within and between proteins by an unnatural amino acid (Uaa) reacting with a natural residue through proximity-enabled bioreactivity. Until now, Uaas have been developed to react mainly with cysteine in proteins. Here we genetically encoded an electrophilic Uaa capabl...

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Veröffentlicht in:ACS chemical biology Jg. 9; H. 9; S. 1956 - 1961
Hauptverfasser: Chen, Xiao-Hua, Xiang, Zheng, Hu, Ying S, Lacey, Vanessa K, Cang, Hu, Wang, Lei
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States American Chemical Society 19.09.2014
Schlagworte:
Amino Acyl-tRNA Synthetases - genetics
Amino Acyl-tRNA Synthetases - metabolism
Cross-Linking Reagents - chemistry
Cysteine - chemistry
Histidine - chemistry
Histidine - genetics
Humans
Lysine - chemistry
Lysine - genetics
Methanosarcina - genetics
Methanosarcina - metabolism
Myoglobin - genetics
Myoglobin - metabolism
Protein Binding
Protein Conformation
Protein Engineering - methods
Receptor, ErbB-2 - chemistry
Receptor, ErbB-2 - metabolism
Recombinant Proteins - chemistry
Recombinant Proteins - metabolism
ISSN:1554-8929, 1554-8937, 1554-8937
Online-Zugang:Volltext
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Zusammenfassung:Covalent bonds can be generated within and between proteins by an unnatural amino acid (Uaa) reacting with a natural residue through proximity-enabled bioreactivity. Until now, Uaas have been developed to react mainly with cysteine in proteins. Here we genetically encoded an electrophilic Uaa capable of reacting with histidine and lysine, thereby expanding the diversity of target proteins and the scope of the proximity-enabled protein cross-linking technology. In addition to efficient cross-linking of proteins inter- and intramolecularly, this Uaa permits direct stapling of a protein α-helix in a recombinant manner and covalent binding of native membrane receptors in live cells. The target diversity, recombinant stapling, and covalent targeting of endogenous proteins enabled by this versatile Uaa should prove valuable in developing novel research tools, biological diagnostics, and therapeutics by exploiting covalent protein linkages for specificity, irreversibility, and stability.
Bibliographie:ObjectType-Article-2
SourceType-Scholarly Journals-1
ObjectType-Correspondence-1
content type line 23
ISSN:1554-8929
1554-8937
1554-8937
DOI:10.1021/cb500453a