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Title: Enhancing the anticoagulant profile of meizothrombin

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.
Authors:
 [1] ;  [1] ;  [2] ;  [1] ;  [1]
  1. Saint Louis Univ. School of Medicine, St. Louis, MO (United States)
  2. Argonne National Lab. (ANL), Argonne, IL (United States)
Publication Date:
Grant/Contract Number:
AC02-06CH11357; 15SDG25550094; HL049413; HL139554
Type:
Accepted Manuscript
Journal Name:
Biomolecular Concepts
Additional Journal Information:
Journal Volume: 9; Journal Issue: 1; Journal ID: ISSN 1868-5021
Publisher:
de Gruyter
Research Org:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org:
USDOE Office of Science (SC); American Heart Association; National Institutes of Health (NIH)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; enzxyme specificity; protein engineering; thrombin
OSTI Identifier:
1504767

Stojanovski, Bosko M., Pelc, Leslie A., Zuo, Xiaobing, Pozzi, Nicola, and Cera, Enrico Di. Enhancing the anticoagulant profile of meizothrombin. United States: N. p., Web. doi:10.1515/bmc-2018-0016.
Stojanovski, Bosko M., Pelc, Leslie A., Zuo, Xiaobing, Pozzi, Nicola, & Cera, Enrico Di. Enhancing the anticoagulant profile of meizothrombin. United States. doi:10.1515/bmc-2018-0016.
Stojanovski, Bosko M., Pelc, Leslie A., Zuo, Xiaobing, Pozzi, Nicola, and Cera, Enrico Di. 2018. "Enhancing the anticoagulant profile of meizothrombin". United States. doi:10.1515/bmc-2018-0016. https://www.osti.gov/servlets/purl/1504767.
@article{osti_1504767,
title = {Enhancing the anticoagulant profile of meizothrombin},
author = {Stojanovski, Bosko M. and Pelc, Leslie A. and Zuo, Xiaobing and Pozzi, Nicola and Cera, Enrico Di},
abstractNote = {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.},
doi = {10.1515/bmc-2018-0016},
journal = {Biomolecular Concepts},
number = 1,
volume = 9,
place = {United States},
year = {2018},
month = {12}
}

Works referenced in this record: