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Cascading into the Thrombin‐Thrombomodulin Complex
Author(s) -
Tidemann Cole,
Beekman Brady,
Leichtfuss Amanda,
Parsons Alex,
Opheim Jonathan,
Garb Ashley,
Henke Noah,
Garb Jodie,
Sood Rashmi
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.lb237
Subject(s) - thrombomodulin , thrombin , protein c , discovery and development of direct thrombin inhibitors , fibrinogen , protease , chemistry , platelet , biochemistry , microbiology and biotechnology , medicine , immunology , biology , enzyme
According to the Centers for Disease Control every year more than 60,000 Americans die of excessive blood clots or thrombophilia, and many more suffer from this disorder. Clotting disorders pose unique problems for women because of their impact on reproductive health and pregnancy. Thrombin, a protease that cleaves fibrinogen and activates platelets, plays a key role in the generation of blood clots. Several mechanisms prevent excessive thrombin activity. Thrombin that diffuses away from the clot binds to its receptor, thrombomodulin. Thrombomodulin‐bound thrombin can no longer generate blood clots. Instead, it cleaves and activates Protein C which shuts down further thrombin generation. The substitution Gln387Pro in thrombomodulin inhibits Protein C activation and interferes with this feed‐back inhibition. The Laconia SMART (Students Modeling A Research Topic) Team used 3D printing technology to model thrombin in association with thrombomodulin. Amino acid residues within the catalytic site (Ser195, His57, and Asp102) and the two substrate binding sites, exosite I (Lys36‐Arg77), and exosite II (Arg 93‐Lys240 of thrombin, involved in these interactions are highlighted. Understanding the relation between structure and function of the thrombin‐thrombomodulin complex may lead to new therapeutics for clotting disorders. This work was supported by a grant from NIH‐CTSA UL1RR031973 .