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PDBsum entry 1lhf
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Complex (serine protease/inhibitor)
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PDB id
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1lhf
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Kinetic and crystallographic studies of thrombin with ac-(D)phe-Pro-Boroarg-Oh and its lysine, Amidine, Homolysine, And ornithine analogs.
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Authors
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P.C.Weber,
S.L.Lee,
F.A.Lewandowski,
M.C.Schadt,
C.W.Chang,
C.A.Kettner.
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Ref.
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Biochemistry, 1995,
34,
3750-3757.
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PubMed id
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Abstract
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The X-ray crystallographic structure of Ac-(D)Phe-Pro-boroArg-OH [DuP714, Ki =
0.04 nM; Kettner, C., Mersinger, L., & Knabb, R. (1990) J. Biol. Chem. 265,
18289] complexed with human alpha-thrombin shows the boron atom covalently
bonded to the side-chain oxygen of the active site serine, Ser195. The boron
adopts a nearly tetrahedral geometry, and the boronic acid forms a set of
interactions with the protein that mimic the tetrahedral transition state of
serine proteases. Contributions of the arginine side chain to inhibitor affinity
were examined by synthesis of the ornithine, lysine, homolysine, and amidine
analogs of DuP714. The basic groups interact with backbone carbonyl groups,
water molecules, and an aspartic acid side chain (Asp189) located in the
thrombin S1 specificity pocket. The variation in inhibition constant by 3 orders
of magnitude appears to reflect differences in the energetics of interactions
made with thrombin and differences in ligand flexibility in solution.(ABSTRACT
TRUNCATED AT 250 WORDS)
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