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PDBsum entry 3pwc
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Hydrolase/hydrolase inhibitor
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PDB id
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3pwc
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References listed in PDB file
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Key reference
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Title
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Correlating structure and ligand affinity in drug discovery: a cautionary tale involving second shell residues.
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Authors
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A.Tziridis,
D.Rauh,
P.Neumann,
P.Kolenko,
A.Menzel,
U.Bräuer,
C.Ursel,
P.Steinmetzer,
J.Stürzebecher,
A.Schweinitz,
T.Steinmetzer,
M.T.Stubbs.
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Ref.
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Biol Chem, 2014,
395,
891-903.
[DOI no: ]
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PubMed id
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Abstract
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Abstract A high-resolution crystallographic structure determination of a
protein-ligand complex is generally accepted as the 'gold standard' for
structure-based drug design, yet the relationship between structure and affinity
is neither obvious nor straightforward. Here we analyze the interactions of a
series of serine proteinase inhibitors with trypsin variants onto which the
ligand-binding site of factor Xa has been grafted. Despite conservative
mutations of only two residues not immediately in contact with ligands (second
shell residues), significant differences in the affinity profiles of the
variants are observed. Structural analyses demonstrate that these are due to
multiple effects, including differences in the structure of the binding site,
differences in target flexibility and differences in inhibitor binding modes.
The data presented here highlight the myriad competing microscopic processes
that contribute to protein-ligand interactions and emphasize the difficulties in
predicting affinity from structure.
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