1ad8
COMPLEX OF THROMBIN WITH AND INHIBITOR CONTAINING A NOVEL P1 MOIETY
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OverviewOverview
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.
DiseaseDisease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this StructureAbout this Structure
1AD8 is a Protein complex structure of sequences from Hirudo medicinalis and Homo sapiens with and as ligands. Active as Thrombin, with EC number 3.4.21.5 Known structural/functional Site: . Full crystallographic information is available from OCA.
ReferenceReference
Molecular design and characterization of an alpha-thrombin inhibitor containing a novel P1 moiety., Malikayil JA, Burkhart JP, Schreuder HA, Broersma RJ Jr, Tardif C, Kutcher LW 3rd, Mehdi S, Schatzman GL, Neises B, Peet NP, Biochemistry. 1997 Feb 4;36(5):1034-40. PMID:9033393
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