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PDBsum entry 2cv3
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Hydrolase/hydrolase inhibitor
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PDB id
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2cv3
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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 the complex of porcine pancreatic elastase with a trimacrocyclic peptide inhibitor fr901451.
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Authors
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T.Kinoshita,
T.Kitatani,
M.Warizaya,
T.Tada.
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Ref.
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Acta Crystallograph Sect F Struct Biol Cryst Commun, 2005,
61,
808-811.
[DOI no: ]
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PubMed id
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Abstract
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Porcine pancreatic elastase (PPE) resembles the attractive drug target leukocyte
elastase, which has the ability to degrade connective tissue in the body. The
crystal structure of PPE complexed with a novel trimacrocyclic peptide
inhibitor, FR901451, was solved at 1.9 A resolution. The inhibitor occupied the
subsites S3 through S3' of PPE and induced conformational changes in the side
chains of Arg64 and Arg226, which are located at the edges of the
substrate-binding cleft. Structural comparison of five PPE-inhibitor complexes,
including the FR901451 complex and non-ligated PPE, reveals that the residues
forming the S2, S1, S1' and S2' subsites in the cleft are rigid, but the two
arginine residues playing a part in the S3 and S3' subsites are flexible.
Structural comparison of PPE with human leukocyte elastase (HLE) implies that
the inhibitor binds to HLE in a similar manner to the FR901451-PPE complex. This
structural insight may help in the design of potent elastase inhibitors.
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Figure 3.
Figure 3 FR901451 within the 2F[o] - F[c] electron-density map
contoured at the 1.0  level.
The map around Trp9 is discontinuous and ambiguous.
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Figure 4.
Figure 4 Superimposed structures of inhibitors in the crystals.
Thr1-Lys4 of FR901451 (magenta sticks) bind to PPE in a similar
conformation to the linear inhibitor FR136706 (Kinoshita et al.,
2003[Kinoshita, T., Nakanishi, I., Sato, A. & Tada, T. (2003).
Bioorg. Med. Chem. Lett. 13, 21-24.]; displayed as blue sticks).
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The above figures are
reprinted
from an Open Access publication published by the IUCr:
Acta Crystallograph Sect F Struct Biol Cryst Commun
(2005,
61,
808-811)
copyright 2005.
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