The crystal structure of the complex of blood coagulation factor VIIa with soluble tissue factor

Abstract

Blood coagulation is initiated when tissue factor binds to coagulation factor VIIa to give an enzymatically active complex which then activates factors IX and X, leading to thrombin generation and clot formation. We have determined the crystal structure at 2.0-A degrees resolution of active-site-inhibited factor VIIa complexed with the cleaved extracellular domain of tissue factor. In the complex, factor VIIa adopts an extended conformation. This structure provides a basis for understanding many molecular aspects of the initiation of coagulation.

Site‐directed mutagenesis but not γ‐carboxylation of Glu‐35 in factor VIIa affects the association with tissue factor

“…The structure of the fVIIa:TF complex reveals no direct contribution of residue 35 to the interaction with TF [4] and apparently the two relatively conservative substitutions are reasonably tolerated. However, the T35V mutation may distort the a-helical environment of residue 35, perhaps influencing the presentation of Phe-31 and Phe-40 [4], leading to a decreased rate of association. At present, we do not know why the impaired TF binding was not revealed in the clot assay.…”

“…The N-terminal domain, encoded on a separate exon, contains the first 37 amino acid residues including all 10 y-carboxyglutamic acid (Gla) residues [2]. This so-called Gla domain binds seven Ca r+ ions [3,4], an event mediated by the Gla residues, and thereby attains a membrane-interactive ability through the exposure of hydrophobic side chains [4,5]. Studies of the roles of the individual Gla residues in factor IX [6], protein C [7][8][9][10] and prothrombin [11], all of which are homologous to fVII, have been conducted.…”

Interleukin‐6: Structure‐function relationships

“…McKay, 1992 Feng et al, 1996Redfield et al, 1994Powers et al, 1992, 1993Muller et al, 1994Walter et al, 1992aWlodawer et al, 1992Muller et al, 1995Walter et al, 1992bRozwarski et al, 1996Milburn et al, 1993Pandit et al, 1992Hill et al, 1993Zink et al, 1994Lovejoy et al, 1993Lovejoy et al, 1993Lovejoy et al, 1993Robinson et al, 1994de Vos et al, 1992Ultsch et al, 1994Somers et al, 1994Sundstrom et al, 1996Sundstrom et al, 1996 Chantalat et aLc Abdel-Meguid et al, 1987McDonald et al, 1995Walter & Nagahhushan, 1995Zdanov et al, 1996Radhakrishnan et al, 1996Senda et al, 1995Ealick et al, 1991Samudzi et al, 1991Samudzi & Rubin, 1993Livnah et al, 1996de Vos et al, 1992Sundstrom et al, 1996Sundstrom et al, 1996Somers et al, 1994Harlos et al, 1994Muller et al, 1996Banner et al. 1996 "Cytokine or receptor class is shown along with the method of structure determination and resolution where appropriate.…”

“…known structures of the class II cytokine receptors. These are the ligand-bound IFN-y receptor and the ligandbound (Banner et al, 1996) and soluble form (Halos et al, 1994;Muller et al, 1996) of tissue factor. This general conservation of the structural form of the receptors within each class makes it seem likely that the structure of other receptors will be similar to the currently known members of each class.…”

Viscoelasticity and Ultrastructure in Coagulation and Inflammation: Two Diverse Techniques, One Conclusion

“…It primarily initiates physiological coagulation and can trigger arterial and venous thrombosis [ 99 ]. As TF binds to activated factor VII (VIIa), this enzymatically active complex transforms factors IX and X to their active forms (IXa and Xa, respectively) to trigger clot formation by means of thrombin generation [ 100 ].…”