Localization of a Heparin Binding Site in the Catalytic Domain of Factor XIa†

Biochemistry ◽  
2001 ◽  
Vol 40 (25) ◽  
pp. 7569-7580 ◽  
Author(s):  
Karen O. Badellino ◽  
Peter N. Walsh
Keyword(s):  
Binding Site ◽  
Catalytic Domain ◽  
Heparin Binding ◽  
Heparin Binding Site ◽  
Factor Xia

scholarly journals Discovery of Allosteric Modulators of Factor XIa by Targeting Hydrophobic Domains Adjacent to Its Heparin-Binding Site

2013 ◽  
Vol 56 (6) ◽  
pp. 2415-2428 ◽  
Author(s):  
Rajesh Karuturi ◽  
Rami A. Al-Horani ◽  
Shrenik C. Mehta ◽  
David Gailani ◽  
Umesh R. Desai
Keyword(s):  
Binding Site ◽  
Allosteric Modulators ◽  
Heparin Binding ◽  
Heparin Binding Site ◽  
Factor Xia

Characterization of Heparin Binding Site Residues on the Catalytic Domain of Factor XIa

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1018-1018 ◽  
Author(s):  
Likui Yang ◽  
Mao-fu Sun ◽  
Chandrashekhara Manithody ◽  
David Gailani ◽  
Alireza R. Rezaie
Keyword(s):  
Binding Site ◽  
Rate Constants ◽  
Serine Proteases ◽  
Catalytic Domain ◽  
Inhibitory Effect ◽  
Heparin Binding ◽  
Wild Type ◽  
Single Chain ◽  
Factor Xia ◽  
Mutant Forms

Abstract The basic residues of the 170-helix (chymotrypsinogen numbering) in the catalytic domain of the procoagulant serine proteases are known to interact with heparin and facilitate their rapid inhibition by specific plasma serpins. The homologous loop of factor XIa possesses three basic residues (Lys-170, Arg-171 and Arg-173). To investigate the role of these residues in the heparin-mediated inhibition of fXIa by C1-inhibitor (C1-INH) and antithrombin (AT), we expressed the monomeric light chain fragment of fXIa containing only the catalytic domain of the protease in wild-type and mutant forms in which the three basic residues of the 170-helix have been substituted individually, or in combinations, with Ala. The catalytic properties of fXIa derivatives were compared to wild-type fXIa (fXIa-WT) with respect to their ability to hydrolyze the chromogenic substrate S2366 and to undergo inhibition by C1-INH and AT in the absence and presence of heparin. All mutants exhibited normal amidolytic activity, hydrolyzing S2366 with catalytic efficiencies similar to fXIa-WT. All mutants were also inhibited by both C1-INH and AT with normal rate constants in the absence of heparin. However, the heparincatalyzed inhibition of mutants by both serpins differed to varying degrees relative to fXIa-WT, with the Arg-171 to Ala substitution mutant exhibiting ~3-fold lower rate of inhibition by C1-INH and requiring ~3-fold higher concentration of heparin for observing optimal inhibitory effect. In reactions with AT, all three basic residues appeared to make similar contributions to the heparin-catalyzed inhibition of fXIa by the serpin as evidenced by all three mutants exhibiting dramatically lower inhibition rate constants in the presence of heparin. A bell-shaped heparin concentration dependence for the fXIa inhibition by both serpins suggested that the template effect of heparin primarily accounts for the acceleration mechanism. However, a comparison of the heparin bell-shaped dependence inhibition of the dimeric plasma-derived wild-type fXIa with that of the isolated single chain catalytic domain suggested that the optimal concentration of heparin for the acceleration of the protease has been increased from ~50 nM for the dimeric protease to ~250 nM for the isolated catalytic domain, possibly suggesting further contribution to affinity of the fXIaheparin interaction from the Apple-3 domain of the non-catalytic domain on which a binding-site for heparin has been reported.

Antithrombin-mediated Inhibition of Factor Vlla-Tissue Factor Complex by the Synthetic Pentasaccharide Representing the Heparin Binding Site to Antithrombin

1996 ◽  
Vol 76 (01) ◽  
pp. 005-008 ◽  
Author(s):  
Jean Claude Lormeau ◽  
Jean Pascal Herault ◽  
Jean Marc Herbert
Keyword(s):  
Binding Site ◽  
Tissue Factor ◽  
Residual Activity ◽  
Coagulation Factors ◽  
Heparin Binding ◽  
Experimental Conditions ◽  
First Order ◽  
Heparin Binding Site ◽  
Coagulant Activity

SummaryWe examined the effect of the synthetic pentasaccharide representing the minimal binding site of heparin to antithrombin on the antithrombin-mediated inactivation of factor Vila bound to tissue factor. This effect was compared to the effect of unfractionated heparin. Using purified recombinant human coagulation factors and either a clotting or an amidolytic assay for the determination of the residual activity of factor Vila, we showed that the pentasaccharide was an efficient antithrombin-dependent inhibitor of the coagulant activity of tissue factor-factor Vila complex. In our experimental conditions, assuming a mean MW of 14,000 for heparin, the molar pseudo-first order rate constants for ATIII-mediated FVIIa inhibition by ATIII-binding heparin and by the synthetic pentasaccharide were found to be similar with respective values of 104,000 ± 10,500 min-1 and 112,000 ± 12,000 min-1 (mean ± s.e.m., n = 3)

scholarly journals Localization of the major heparin-binding site in fibronectin.

1991 ◽  
Vol 266 (12) ◽  
pp. 7812-7818 ◽  
Author(s):  
F J Barkalow ◽  
J E Schwarzbauer
Keyword(s):  
Binding Site ◽  
Heparin Binding ◽  
Heparin Binding Site

Structural Analysis of the Heparin-Binding Site of the NC1 Domain of Collagen XIV by CD and NMR†,‡

Biochemistry ◽  
1999 ◽  
Vol 38 (20) ◽  
pp. 6479-6488 ◽  
Author(s):  
Roland Montserret ◽  
Elisabeth Aubert-Foucher ◽  
Michael J. McLeish ◽  
Joanna M. Hill ◽  
Damien Ficheux ◽  
...  
Keyword(s):  
Structural Analysis ◽  
Binding Site ◽  
Heparin Binding ◽  
Heparin Binding Site ◽  
Nc1 Domain

Pulmonary arterial thrombosis in a neonate with homozygous deficiency of antithrombin III: successful outcome following pulmonary thrombectomy and infusions of antithrombin III concentrate

2000 ◽  
Vol 10 (3) ◽  
pp. 275-278 ◽  
Author(s):  
K. Roman ◽  
E. Rosenthal ◽  
R. Razavi
Keyword(s):  
Binding Site ◽  
Arterial Thrombosis ◽  
Antithrombin Iii ◽  
Pulmonary Trunk ◽  
Successful Outcome ◽  
Heparin Binding ◽  
The Third ◽  
Heparin Binding Site ◽  
Surgical Thrombectomy ◽  
Pulmonary Arterial

AbstractWe report a newborn male who presented with severe central cyanosis on the third day of life. Partial thrombotic obstruction of the pulmonary trunk secondary to Antithrombin III (homozygous defect of heparin binding site) deficiency was subsequently diagnosed. Surgical thrombectomy, and infusions of Antithrombin III concentrate, led to a successful outcome. We postulate that intrauterine thrombosis occurred to give this unusual presentation.

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