title: Structure of the extracellular domain of human tissue factor: location of the factor VIIa binding site.
abstract: Tissue factor, the obligate cofactor for coagulation factor VII, plays an essential role in hemostasis by initiating the extrinsic pathway of blood coagulation upon vascular damage, making it a promising target for new anticoagulant therapies in the treatment of thrombosis and sepsis. The three-dimensional structure of the extracellular domain of tissue factor, determined by X-ray crystallography at a resolution of 2.4 A, consists of two domains of approximately equal size, with a topology characteristic of fibronectin type III modules. Comparison of tissue factor with the extracellular domain of the growth hormone receptor, which belongs to the same receptor superfamily, shows that the relative orientation between these domains as well as the domain-domain interface is very different. These differences have dramatic consequences for the residues in tissue factor that are homologous to the binding determinants of the growth hormone receptor. Alanine-scanning mutagenesis has identified tissue factor residues important for factor VIIa binding. The structure shows that the binding site is located in the domain-domain interface region but on the opposite side of the molecule compared to the growth hormone receptor, with the binding determinants residing on beta-strands rather than on loops.
authors.affiliation: Department of Protein Engineering, Genentech, Inc., South San Francisco, California 94080.
authors.forename: Y A
authors.initials: YA
authors.lastname: Muller
authors.forename: M H
authors.initials: MH
authors.lastname: Ultsch
authors.forename: R F
authors.initials: RF
authors.lastname: Kelley
authors.forename: A M
authors.initials: AM
authors.lastname: de Vos
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D015942:Factor VIIa / Q000378:metabolism; D006801:Humans; D016296:Mutagenesis; D011487:Protein Conformation; D013925:Thromboplastin / Q000737:chemistry* / Q000378:metabolism
chemical_list: D013925:Thromboplastin; D015942:Factor VIIa