A Synthetic Analog of Fibrinogen α27–50 Is an Inhibitor of Thrombin

Binnie, Cameron G.; Lord, Susan T.

doi:10.1055/s-0038-1647477

Cited by 33 publications

(30 citation statements)

References 7 publications

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“…The latter is a well-characterized nonsubstrate binding phenomenon in the interaction between human thrombin and human fibrin that is attributed to (1) residual thrombin binding at or near the substrate interaction site in the fibrin E-domain, and (2) binding at a higher-affinity binding site in the ␥Ј-variant of the fibrinogen ␥-chain. [33][34][35][36][37] The mouse ␥-chain does not contain the thrombin-binding sequence motif, 38 thus predicting the absence of a high-affinity thrombin-fibrin interaction. A preliminary analysis of binding of mouse thrombin to mouse fibrinogen failed to produce evidence for the existence of a high-affinity thrombin binding component in mouse fibrin (data not shown), consistent with the above prediction.…”

Section: Discussionmentioning

confidence: 99%

Cause-effect relation between hyperfibrinogenemia and vascular disease

Kerlin

Cooley

Isermann

et al. 2004

Blood

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Elevated plasma levels of fibrinogen are associated with the presence of cardiovascular disease, but it is controversial whether elevated fibrinogen causally imparts an increased risk, and as such is a true modifier of cardiovascular disease, or is merely associated with disease. By investigating a transgenic mouse model of hyperfibrinogenemia, we show that elevated plasma fibrinogen concentration IntroductionNumerous epidemiological studies have documented the association of elevated plasma fibrinogen levels with cardiovascular disease. [1][2][3][4][5][6][7] Cross-sectional prospective studies imply that elevated plasma fibrinogen levels are an independent and predictive parameter for increased risk of coronary artery disease, stroke, and peripheral vascular disease. The magnitude of the increase in fibrinogen levels correlates with the presence and severity of peripheral arterial disease, the extent of myocardial necrosis in infarcted patients, and cerebrovascular accidents. The disease risk associated with hyperfibrinogenemia is disproportionally augmented in those individuals with the highest fibrinogen levels, indicating a threshold effect. Notwithstanding its recognized value as a marker for the presence of cardiovascular disease, it remains controversial whether an elevated fibrinogen level itself imparts an increased risk, and therefore represents a true modifier of vascular disease, or is merely associated with disease. Fibrinogen production in the liver is regulated by cytokines and is greatly enhanced in the acute phase response to infection and other inflammatory processes. [8][9][10][11] It is therefore possible that moderately elevated fibrinogen levels simply report a state of inflammation associated with vascular disease. On the other hand, augmented fibrinogen levels, per se, could alter the hemodynamic properties of blood or enhance concentration driven enzyme-substrate interactions between thrombin, fibrinogen, and platelets, and thus lead to increased intravascular fibrin deposition and thrombosis. These views are not mutually exclusive, as augmentation of fibrinogen levels secondary to an inflammatory challenge could nevertheless amplify or accelerate the disease process. Moreover, fibrinogen and fibrin degradation products might in turn enhance the inflammatory aspect of vascular lesions by regulating cytokine production and leukocyte-endothelial interactions. [12][13][14][15][16][17] Recently described genetically altered mice with chronically increased plasma fibrinogen levels in the absence of underlying inflammation provide a novel experimental tool to investigate the cause-effect relationship between hyperfibrinogenemia and vascular disease. 18 The mutant mouse strain (hereafter referred to as Hifib mice) was derived by pronuclear oocyte microinjection of the entire mouse fibrinogen locus, including all 3 fibrinogen chains as well as several kilobases of flanking sequence. The added transgenic fibrinogen allele is inherited in a Mendelian fashion, and the mice were reported to exhibit...

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Section: Discussionmentioning

confidence: 99%

Cause-effect relation between hyperfibrinogenemia and vascular disease

Kerlin

Cooley

Isermann

et al. 2004

Blood

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“…All the sites on fibrinogen A␣ that bind to thrombin are believed to be located within the first 50 residues of the A␣ chain. 30,31 Little is known, however, about the conformation of FbgA␣ in the vicinity of the R16-G17 cleavage site because many of the NMR and X-ray studies published thus far have involved the use of native thrombin and hydrolyzable peptide substrates. During these experiments, the enzyme cleaves the peptide substrate, and hence structural information is obtained only for the hydrolyzed product.…”

Section: Introductionmentioning

confidence: 99%

New general approach for determining the solution structure of a ligand bound weakly to a receptor: structure of a fibrinogen A?-like peptide bound to thrombin(S195A) obtained using NOE distance constraints and an ECEPP/3 flexible docking program

et al. 1999

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A new approach incorporating flexible docking simulations and NMR data is presented for calculating the bound conformation of a ligand that interacts weakly with an enzyme. This approach consists of sampling directly the conformation of a flexible ligand inside a receptor active site containing surrounding flexible loops. To make this sampling efficient, a ligand-growing procedure has been adopted. Optimization of the ECEPP/3-plus-NOE constraint function is carried out by using a collective variable Monte Carlo minimization technique. Numerous energy minimizations are made possible for such a large system by using a Bezier splines energy grid technique. This new flexible docking approach was applied to determine the structure of a fibrinogen Aalpha-like peptide (7DFLAEGGGVRGPRV20) bound to an active site mutant of thrombin [thrombin(S195A)]. Structure calculations of the bound ligand, using 2D-transferred NOESY distance constraints in the DIANA program, showed that the N-terminal portion of the peptide (D7-R16) involves a chain reversal, whereas the C-terminal portion (G17-V20) adopts a fold that exists in several different orientations. In addition, the ECEPP/3 flexible docking package was used to assess the conformational variability of the ligand and surrounding 60D-insertion loop of thrombin. Amino acid residues (17-20) of the peptide interact with a region of the enzyme that exhibits broad specificity, with a preferred direction between the 60D-insertion loop and Pro37 of thrombin.

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“…The N-terminal fragment of Aα chain is responsible for binding with thrombin and formation of fibrin polymerization sites 13. Zhang et al had expressed N-terminal truncated Aα chain in COS1 cells and found that removal of the first 41 amino acids of Aα chain (Aα 1–41) did not affect the assembly and secretion of dimeric fibrinogen 14.…”

Section: Discussionmentioning

confidence: 99%