Showing papers by "James A. Huntington published in 2004"
TL;DR: A notably close contact interface, comprised of extensive active site and exosite interactions, explains, in molecular detail, the basis of the antithrombotic properties of therapeutic heparin.
Abstract: The maintenance of normal blood flow depends completely on the inhibition of thrombin by antithrombin, a member of the serpin family. Antithrombin circulates at a high concentration, but only becomes capable of efficient thrombin inhibition on interaction with heparin or related glycosaminoglycans. The anticoagulant properties of therapeutic heparin are mediated by its interaction with antithrombin, although the structural basis for this interaction is unclear. Here we present the crystal structure at a resolution of 2.5 A of the ternary complex between antithrombin, thrombin and a heparin mimetic (SR123781). The structure reveals a template mechanism with antithrombin and thrombin bound to the same heparin chain. A notably close contact interface, comprised of extensive active site and exosite interactions, explains, in molecular detail, the basis of the antithrombotic properties of therapeutic heparin.
367 citations
TL;DR: The structural requirements for small peptides to competitively bind to and block the s4A position to prevent this intermolecular linkage and polymerisation are defined and the rational design of synthetic blocking-peptides small enough to be suitable for mimetic design is allowed.
88 citations
TL;DR: The data support the conclusion that missense mutations affecting the shutter region of serpins have specific conformational effects resulting in the formation of mutant oligomers, and suggests that the oligomers also have new and undefined pathological properties that could be exacerbated by pregnancy or infection.
62 citations
TL;DR: It is concluded that the heparin-binding mechanism of HCII is closely analogous to that of AT and that the induced fit mechanism suggests the potential design or discovery of specific HCII agonists.
60 citations
TL;DR: The 2.5-Å crystal structure of human E217K thrombin is described, which displays a dramatic restructuring of the geometry of the active site and may represent the Na+-free, catalytically inert “slow” form.
52 citations
TL;DR: The results confirm the key structural role of the P17 glutamate in serpins and cause conformational instability and polymerization in 3 serpins: Drosophila necrotic, human &agr;1-antitrypsin, and human HCII, which explains their plasma deficiency.
Abstract: Background— Heparin cofactor II (HCII) is a hepatic serpin with significant antithrombin activity that has been implicated in coagulation, inflammation, atherosclerosis, and wound repair. Recent data obtained in mice lacking HCII suggest that this serpin might inhibit thrombosis in the arterial circulation. However, the clinical relevance and molecular mechanisms associated with deficiency of HCII in humans are unclear. Methods and Results— We studied the first family with homozygous HCII deficiency, identifying a Glu428Lys mutation affecting a conserved glutamate at the hinge (P17) of the reactive loop. No carrier reported arterial thrombosis, and only 1 homozygous HCII-deficient patient developed severe deep venous thrombosis, but she also had a de novo Glu100Stop nonsense truncation in the antithrombin gene. Conclusions— Our results confirm the key structural role of the P17 glutamate in serpins. The same mutation causes conformational instability and polymerization in 3 serpins: Drosophila necrotic, h...
45 citations
TL;DR: It is concluded that AT hinge region extension is the activating conformational change for inhibition of factors IXa and Xa, and proposed models for the progressive and activated AT Michaelis complexes with thrombin, factor XA, and factor IXa are proposed.
35 citations
TL;DR: It is concluded that wild-type Glu-381 interactions stabilize the activated state and decreases the energy barrier to full loop insertion in antithrombin, suggesting new stabilizing interactions in the native structure.
17 citations
TL;DR: It is concluded that the heparin binding mechanism of HCII is closely analogous to that of AT, and that the design or discovery of high affinity, HCII-specific GAGs is thus feasible.
5 citations