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PDBsum entry 4os6
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Hydrolase/hydrolase inhibitor
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PDB id
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4os6
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References listed in PDB file
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Key reference
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Title
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Dithiol amino acids can structurally shape and enhance the ligand-Binding properties of polypeptides.
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Authors
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S.Chen,
R.Gopalakrishnan,
T.Schaer,
F.Marger,
R.Hovius,
D.Bertrand,
F.Pojer,
C.Heinis.
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Ref.
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Nat Chem, 2014,
6,
1009-1016.
[DOI no: ]
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PubMed id
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Abstract
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The disulfide bonds that form between two cysteine residues are important in
defining and rigidifying the structures of proteins and peptides. In
polypeptides containing multiple cysteine residues, disulfide isomerization can
lead to multiple products with different biological activities. Here, we
describe the development of a dithiol amino acid (Dtaa) that can form two
disulfide bridges at a single amino acid site. Application of Dtaas to a serine
protease inhibitor and a nicotinic acetylcholine receptor inhibitor that contain
disulfide constraints enhanced their inhibitory activities 40- and 7.6-fold,
respectively. X-ray crystallographic and NMR structure analysis show that the
peptide ligands containing Dtaas have retained their native tertiary structures.
We furthermore show that replacement of two cysteines by Dtaas can avoid the
formation of disulfide bond isomers. With these properties, Dtaas are likely to
have broad application in the rational design or directed evolution of peptides
and proteins with high activity and stability.
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