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PDBsum entry 4hgc
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Hydrolase/hydrolase inhibitor
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PDB id
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4hgc
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References listed in PDB file
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Key reference
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Title
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Structure of a proteolytically resistant analogue of (nlys)5sfti-1 in complex with trypsin: evidence for the direct participation of the ser214 carbonyl group in serine protease-Mediated proteolysis.
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Authors
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S.Krzywda,
M.Jaskolski,
K.Rolka,
M.J.Stawikowski.
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Ref.
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Acta Crystallogr D Biol Crystallogr, 2014,
70,
668-675.
[DOI no: ]
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PubMed id
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Abstract
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Peptide-peptoid hybrids are found to be potent inhibitors of serine proteases.
These engineered peptidomimetics benefit from both types of units of the
biopolymeric structure: the natural inhibitor part serves as a good binding
template, while the P1-positioned peptoid component provides complete resistance
towards proteolysis. In this report, the mechanism of proteolytic resistance of
a P1 peptoid-containing analogue is postulated based on the crystal structure of
the (NLys)(5)-modified sunflower trypsin inhibitor SFTI-1 in complex with bovine
trypsin solved at 1.29 Å resolution. The structural differences between the
(NLys)(5)SFTI-1-trypsin complex and the native SFTI-1-trypsin complex are
surprisingly small and reveal the key role of the carbonyl group of the Ser214
residue of the enzyme, which is crucial for binding of the inhibitor and plays a
crucial role in proteolysis mediated by serine proteases. The incorporated NLys5
peptoid residue prevents Ser214 from forming a hydrogen bond to the P1 residue,
and in turn Gln192 does not form a hydrogen bond to the carbonyl group of the P2
residue. It also increases the distance between the Ser214 carbonyl group and
the Ser195 residue, thus preventing proteolysis. The hybrid inhibitor structure
reported here provides insight into protein-protein interaction, which can be
efficiently and selectively probed with the use of peptoids incorporated within
endogenous peptide ligands.
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