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Title: Crystal structure of prethrombin-1

Abstract

Prothrombin is the zymogen precursor of the clotting enzyme thrombin, which is generated by two sequential cleavages at R271 and R320 by the prothrombinase complex. The structure of prothrombin is currently unknown. Prethrombin-1 differs from prothrombin for the absence of 155 residues in the N-terminal domain and is composed of a single polypeptide chain containing fragment 2 (residues 156-271), A chain (residues 272-320), and B chain (residues 321-579). The X-ray crystal structure of prethrombin-1 solved at 2.2-{angstrom} resolution shows an overall conformation significantly different (rmsd = 3.6 {angstrom}) from that of its active form meizothrombin desF1 carrying a cleavage at R320. Fragment 2 is rotated around the y axis by 29{sup o} and makes only few contacts with the B chain. In the B chain, the oxyanion hole is disrupted due to absence of the I16-D194 ion pair and the Na{sup +} binding site and adjacent primary specificity pocket are highly perturbed. A remarkable feature of the structure is that the autolysis loop assumes a helical conformation enabling W148 and W215, located 17 {angstrom} apart in meizothrombin desF1, to come within 3.3 {angstrom} of each other and completely occlude access to the active site. These findings suggest that the zymogenmore » form of thrombin possesses conformational plasticity comparable to that of the mature enzyme and have significant implications for the mechanism of prothrombin activation and the zymogen {yields} protease conversion in trypsin-like proteases.« less

Authors:
; ;  [1]
  1. St. Louis-MED
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1002868
Resource Type:
Journal Article
Journal Name:
Proc. Natl. Acad. Sci. USA
Additional Journal Information:
Journal Volume: 107; Journal Issue: (45) ; 11, 2010; Journal ID: ISSN 0027-8424
Country of Publication:
United States
Language:
ENGLISH
Subject:
36 MATERIALS SCIENCE; AUTOLYSIS; CHAINS; CLEAVAGE; CRYSTAL STRUCTURE; ENZYMES; ION PAIRS; PLASTICITY; POLYPEPTIDES; PRECURSOR; PROTHROMBIN; RESIDUES; RESOLUTION; SPECIFICITY; THROMBIN

Citation Formats

Chen, Zhiwei, Pelc, Leslie A, and Di Cera, Enrico. Crystal structure of prethrombin-1. United States: N. p., 2010. Web. doi:10.1073/pnas.1010262107.
Chen, Zhiwei, Pelc, Leslie A, & Di Cera, Enrico. Crystal structure of prethrombin-1. United States. https://doi.org/10.1073/pnas.1010262107
Chen, Zhiwei, Pelc, Leslie A, and Di Cera, Enrico. 2010. "Crystal structure of prethrombin-1". United States. https://doi.org/10.1073/pnas.1010262107.
@article{osti_1002868,
title = {Crystal structure of prethrombin-1},
author = {Chen, Zhiwei and Pelc, Leslie A and Di Cera, Enrico},
abstractNote = {Prothrombin is the zymogen precursor of the clotting enzyme thrombin, which is generated by two sequential cleavages at R271 and R320 by the prothrombinase complex. The structure of prothrombin is currently unknown. Prethrombin-1 differs from prothrombin for the absence of 155 residues in the N-terminal domain and is composed of a single polypeptide chain containing fragment 2 (residues 156-271), A chain (residues 272-320), and B chain (residues 321-579). The X-ray crystal structure of prethrombin-1 solved at 2.2-{angstrom} resolution shows an overall conformation significantly different (rmsd = 3.6 {angstrom}) from that of its active form meizothrombin desF1 carrying a cleavage at R320. Fragment 2 is rotated around the y axis by 29{sup o} and makes only few contacts with the B chain. In the B chain, the oxyanion hole is disrupted due to absence of the I16-D194 ion pair and the Na{sup +} binding site and adjacent primary specificity pocket are highly perturbed. A remarkable feature of the structure is that the autolysis loop assumes a helical conformation enabling W148 and W215, located 17 {angstrom} apart in meizothrombin desF1, to come within 3.3 {angstrom} of each other and completely occlude access to the active site. These findings suggest that the zymogen form of thrombin possesses conformational plasticity comparable to that of the mature enzyme and have significant implications for the mechanism of prothrombin activation and the zymogen {yields} protease conversion in trypsin-like proteases.},
doi = {10.1073/pnas.1010262107},
url = {https://www.osti.gov/biblio/1002868}, journal = {Proc. Natl. Acad. Sci. USA},
issn = {0027-8424},
number = (45) ; 11, 2010,
volume = 107,
place = {United States},
year = {2010},
month = {11}
}