2hnt
CRYSTALLOGRAPHIC STRUCTURE OF HUMAN GAMMA-THROMBIN
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OverviewOverview
In an effort to prepare crystals and determine the structure of, alpha-thrombin complexed to a synthetic peptide inhibitor (MDL-28050) of, the hirudin 54-65 COOH-terminal region, it was discovered that the, crystals were not those of the complex but of gamma-thrombin. Gel, electrophoresis studies revealed that autolytic degradation had occurred, prior to crystallization. NH2-terminal sequence analysis of these, autolytic fragments confirmed the gamma-thrombin product (cleavages at, Arg75-Tyr76 and/or Arg77A-Asn78, and Lys149E-Gly150; chymotrypsinogen, numbering) with a minor amount of another autolysis product, beta-thrombin, (first two cleavages only). The final structure has an R-factor of 0.156, for 7.0-2.5-A data, and includes 186 water molecules. A comparison of, gamma-thrombin with the thrombin structure in the alpha-thrombin-hirugen, complex revealed that the two structures agreed well (r.m.s. delta = 0.39, A for main chain atoms). These structures possess uninhibited active sites, where the disposition of the catalytic triad residues is nearly identical., The electron density in the vicinity of the gamma-thrombin cleavage, regions is poor, and only becomes well-defined several residues prior to, and after the actual cleavage sites. The extensive disorder evoked by, beta-cleavage(s) in the Lys70-Glu80 loop region indicates that this part, of the molecule is severely disrupted by autolysis and is the reason, exosite functions are dramatically impaired in beta-and gamma-thrombin., Since autolysis did not lead to a major reorganization of the folded, structure of alpha-thrombin, the likely structural features of the, interaction of thrombin substrate with thrombin enzyme during, beta-cleavage have been modeled by docking the exosite region of one, molecule at the active site of another.
DiseaseDisease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this StructureAbout this Structure
2HNT is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Crystallographic structure of human gamma-thrombin., Rydel TJ, Yin M, Padmanabhan KP, Blankenship DT, Cardin AD, Correa PE, Fenton JW 2nd, Tulinsky A, J Biol Chem. 1994 Sep 2;269(35):22000-6. PMID:8071320
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