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PDBsum entry 1ad8
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Hydrolase/hydrolase inhibitor
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PDB id
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1ad8
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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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Molecular design and characterization of an alpha-Thrombin inhibitor containing a novel p1 moiety.
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Authors
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J.A.Malikayil,
J.P.Burkhart,
H.A.Schreuder,
R.J.Broersma,
C.Tardif,
L.W.Kutcher,
S.Mehdi,
G.L.Schatzman,
B.Neises,
N.P.Peet.
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Ref.
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Biochemistry, 1997,
36,
1034-1040.
[DOI no: ]
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PubMed id
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Abstract
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An inhibitor of alpha-thrombin was designed on the basis of the X-ray crystal
structures of thrombin and trypsin. The design strategy employed the geometric
and electrostatic differences between the specificity pockets of the two
enzymes. These differences arise due to the replacement of Ser 190 in trypsin by
Ala 190 in thrombin. The new inhibitor contained a tryptophan side chain instead
of the arginine side chain that is present in the prototypical thrombin
inhibitors. This inhibitor had a Ki value of 0.25 microM, displayed more than
400-fold specificity for thrombin over trypsin, and doubled the rat plasma APTT
at a concentration of 44.9 microM. The X-ray crystal structure of the
inhibitor/alpha-thrombin complex was determined. This represents the first
reported three-dimensional structure of a thrombin/ inhibitor complex where the
specificity pocket of the enzyme is occupied by a chemical moiety other than a
guanidino or an amidino group. As was predicted by the molecular model, the
tryptophan side chain docks into the specificity pocket of the enzyme. This
finding is in contrast with the indole binding region of thrombin reported
earlier [Berliner, L. J., & Shen, Y. Y. L. (1977) Biochemistry 16,
4622-4626]. The lower binding affinity of the new inhibitor for trypsin,
compared to that for thrombin, appears to be due to (i) the extra energy
required to deform the smaller specificity pocket of trypsin to accommodate the
bulky indole group and (ii) the favorable electrostatic interactions of the
indole group with the more hydrophobic specificity pocket of thrombin. The
neutral indole group may be of pharmacological significance because the severe
hypotension and respiratory distress observed following the administration of
some thrombin inhibitors have been linked to the positively charged guanidino or
amidino functionalities.
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