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PDBsum entry 4phn
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References listed in PDB file
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Key reference
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Title
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The structural basis of differential inhibition of human calpain by indole and phenyl α-Mercaptoacrylic acids.
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Authors
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S.E.Adams,
P.J.Rizkallah,
D.J.Miller,
E.J.Robinson,
M.B.Hallett,
R.K.Allemann.
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Ref.
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J Struct Biol, 2014,
187,
236-241.
[DOI no: ]
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PubMed id
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Abstract
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Excessive activity of neutrophils has been linked to many pathological
conditions, including rheumatoid arthritis, cancer and Alzheimer's disease.
Calpain-I is a Ca(2+)-dependent protease that plays a key role in the
extravasation of neutrophils from the blood stream prior to causing damage
within affected tissues. Inhibition of calpain-I with small molecule
mercaptoacrylic acid derivatives slows the cell spreading process of live
neutrophils and so these compounds represent promising drug leads. Here we
present the 2.05 and 2.03Å co-crystal X-ray structures of the pentaEF hand
region, PEF(S), from human calpain with (Z)-3-(4-chlorophenyl)-2-mercaptoacrylic
acid and (Z)-3-(5-bromoindol-3-yl)-2-mercaptoacrylic acid. In both structures,
the α-mercaptoacrylic acid derivatives bind between two α-helices in a
hydrophobic pocket that is also exploited by a leucine residue of the endogenous
regulatory calpain inhibitor calpastatin. Hydrophobic interactions between the
aromatic rings of both inhibitors and the aliphatic residues of the pocket are
integral for tight binding. In the case of
(Z)-3-(5-bromoindol-3-yl)-2-mercaptoacrylic acid, hydrogen bonds form between
the mercaptoacrylic acid substituent lying outside the pocket and the protein
and the carboxylate group is coplanar with the aromatic ring system. Multiple
conformations of (Z)-3-(5-bromoindol-3-yl)-2-mercaptoacrylic acid were found
within the pocket. The increased potency of
(Z)-3-(5-bromoindol-3-yl)-2-mercaptoacrylic acid relative to
(Z)-3-(4-chlorophenyl)-2-mercaptoacrylic acid may be a consequence of the indole
group binding more deeply in the hydrophobic pocket of PEF(S) than the phenyl
ring.
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