Enhancing the anticoagulant profile of meizothrombin

Stojanovski, Bosko M.; Pelc, Leslie A.; Zuo, Xiaobing; Pozzi, Nicola; Cera, Enrico Di

doi:10.1515/bmc-2018-0016

Title: Enhancing the anticoagulant profile of meizothrombin

Journal Article · 26 December 2018 · Biomolecular Concepts

DOI: https://doi.org/10.1515/bmc-2018-0016 · OSTI ID:1504767

Stojanovski, Bosko M. ^[1]; Pelc, Leslie A. ^[1]; Zuo, Xiaobing ^[2]; Pozzi, Nicola ^[1]; Cera, Enrico Di ^[1]

Saint Louis Univ. School of Medicine, St. Louis, MO (United States)
Argonne National Lab. (ANL), Argonne, IL (United States)

Meizothrombin is an active intermediate generated during the proteolytic activation of prothrombin to thrombin in the penultimate step of the coagulation cascade. Structurally, meizothrombin differs from thrombin because it retains the auxiliary Gla domain and two kringles. Functionally, meizothrombin shares with thrombin the ability to cleave procoagulant (fibrinogen), prothrombotic (PAR1) and anticoagulant (protein C) substrates, although its specificity toward fibrinogen and PAR1 is less pronounced. In this study we report information on the structural architecture of meizothrombin resolved by SAXS and single molecule FRET as an elongated arrangement of its individual domains. In addition, we show the properties of a meizothrombin construct analogous to the anticoagulant thrombin mutant W215A/E217A currently in Phase I for the treatment of thrombotic complications and stroke. The findings reveal new structural and functional aspects of meizothrombin that advance our understanding of a key intermediate of the prothrombin activation pathway.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC); American Heart Association; National Institutes of Health (NIH)

Grant/Contract Number:: AC02-06CH11357; 15SDG25550094; HL049413; HL139554

OSTI ID:: 1504767

Journal Information:: Biomolecular Concepts, Vol. 9, Issue 1; ISSN 1868-5021

Publisher:: de GruyterCopyright Statement

Country of Publication:: United States

Language:: English

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