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PDBsum entry 3h8c
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References listed in PDB file
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Key reference
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Title
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A combined crystallographic and molecular dynamics study of cathepsin l retrobinding inhibitors.
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Authors
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R.T.Shenoy,
S.F.Chowdhury,
S.Kumar,
L.Joseph,
E.O.Purisima,
J.Sivaraman.
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Ref.
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J Med Chem, 2009,
52,
6335-6346.
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PubMed id
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Abstract
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We report the crystal structures of three noncovalent retrobinding inhibitors in
complex with mature cathepsin L up to resolutions of 2.5, 1.8, and 2.5 A,
respectively. These inhibitors were Bpa-(Nepsilon-Bpa)Lys-DArg-Tyr-Npe,
Bpa-(Nepsilon-Bpa)Lys-DArg-Phe-Npe, and Bpa-MCys-DArg-Phe-Npe, where Bpa =
biphenylacetyl and Pea = N-phenylethyl. These were selected to clarify the
binding mode of the biphenyl groups in the S' subsites because the addition of a
second biphenyl does not improve potency. Examination of the symmetry-related
monomers in the crystal structures revealed inhibitor-inhibitor crystal packing
interactions. Molecular dynamics simulations were then used to explore the
structure and dynamical behavior of the isolated protein-ligand complexes in
solution. In the simulations, the backbone biphenyl groups for all three
inhibitors ended up in the same location despite having started out in different
orientations in the initial crystal structure conformations. The lack of
improved potency of the larger inhibitors over the smaller one is attributed to
a correspondingly greater entropic cost of binding.
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