THE CRYSTAL-STRUCTURE OF THE EXTRACELLULAR DOMAIN OF HUMAN TISSUE FACTOR REFINED TO 1.7 ANGSTROM RESOLUTION

Exposure of blood to cells expressing tissue factor results in formati on of a high-affinity complex with factor VIIa, initiating the extrins ic pathway of blood coagulation by the activation of factors IX and X. The structure of the extracellular portion of tissue factor was refin ed to a crystallographic X-value of 20.4% to a resolution of 1.69 Angs trom against synchrotron data collected from a flash-frozen crystal. T he structure consists of two fibronectin type III modules whose hydrop hobic cores merge in the domain-domain interface, suggesting that the extracellular portion serves as a relatively rigid template for factor VIIa binding. Analysis of the hydrophobic core of each individual mod ule identifies a cluster of residues forming a packing motif centered on Trp25 which appears to be characteristic for fibronectin type III m odules. Comparison of the structure to that of the human growth hormon e receptor, which belongs to a different class (class I) of the same c ytokine receptor superfamily, shows that the structure of the individu al domains is very similar but that the relative domain-domain orienta tion differs greatly Even though the WSXWS box characteristic of the c lass I cytokine receptors is not present in tissue factor, the analogo us residues have the identical polyproline helical conformation. Mappi ng of residues important for biological activity on the structure show s that all these are located on P-strands in a small number of distinc t clusters, on the opposite side of the molecule compared to the ligan d binding determinants of the growth hormone receptor. (C) 1996 Academ ic Press Limited.