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MOLECULAR BASIS FOR THE INHIBITION OF HUMAN ALPHA-THROMBIN BY THE MACROCYCLIC PEPTIDE CYCLOTHEONAMIDE A
OverviewOverview
The macrocyclic peptide cyclotheonamide A (CtA), isolated from the marine, sponge Theonella sp., represents an unusual class of serine protease, inhibitor. A complex of this inhibitor with human alpha-thrombin, a, protease central to the bioregulation of thrombosis and hemostasis, was, studied by x-ray crystallography. This work (2.3-A resolution) confirms, the structure of CtA and reveals intimate details about its molecular, recognition within the enzyme active site. Interactions due to the, "Pro-Arg motif" (Arg occupancy of the S1 specificity pocket; formation of, a hydrogen-bonded two-strand antiparallel beta-sheet with Ser214-Gly216), and the alpha-keto amide group of CtA are primarily responsible for, binding to thrombin, with the alpha-keto amide serving as a, transition-state analogue. A special interaction with the "insertion loop", of thrombin (Tyr60A-Thr60I) is manifested through engagement of the, hydroxyphenyl group of CtA with Trp60D as part of an "aromatic stacking, chain." Biochemical inhibition data (Ki values at 37 degrees C) were, obtained for CtA with thrombin and a diverse collection of serine, proteases. Thus, CtA is just a moderate inhibitor of human alpha-thrombin, (Ki = 0.18 microM) but a potent inhibitor of trypsin (Ki = 0.023 microM), and streptokinase (Ki = 0.035 microM). The relative lack of potency of CtA, as a thrombin inhibitor is discussed with respect to certain structural, features of the enzyme complex. We also report the total synthesis of CtA, by a convergent [2 + 3] fragment-condensation approach, to serve the, preparation of cyclotheonamide analogues for structure-function studies.
DiseaseDisease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this StructureAbout this Structure
1TMB is a Protein complex structure of sequences from Homo sapiens with SO3 and FOR as ligands. Active as Thrombin, with EC number 3.4.21.5 Full crystallographic information is available from OCA.
ReferenceReference
Molecular basis for the inhibition of human alpha-thrombin by the macrocyclic peptide cyclotheonamide A., Maryanoff BE, Qiu X, Padmanabhan KP, Tulinsky A, Almond HR Jr, Andrade-Gordon P, Greco MN, Kauffman JA, Nicolaou KC, Liu A, et al., Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):8048-52. PMID:8367461
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