3-DIMENSIONAL STRUCTURE OF HUMAN BASIC FIBROBLAST GROWTH-FACTOR

The three-dimensional structure of human basic fibroblast growth factor (bFGF) has been determined by x-ray crystallography and refined to a crystallographic residual of 17.4% at 2.2-angstrom resolution. The structure was initially solved at a nominal resolution of 2.8 angstrom by multiple isomorphous replacement using three heavy-atom derivatives. Although the map clearly showed the overall fold of the molecule, electron density was not observed for the first 19 amino-terminal and the last 3 carboxyl-terminal amino acids, suggesting that they are disordered. The bFGF crystals were grown from 2.0 M ammonium sulfate at pH 8.1 in space group P1 with cel' dimensions a = 30.9 angstrom, b = 33.4 angstrom, c = 35.9 angstrom,alpha = 59.5-degrees, beta = 72.0-degrees, and gamma = 75.6-degrees. There is one molecule per unit cell and the crystals diffract to spacings beyond 1.9 angstrom. The overall structure of bFGF can be described as a trigonal pyramid with a fold very similar to that reported for interleukin 1-beta, interleukin 1-alpha, and soybean trypsin inhibitor. An apparent sulfate ion is bound within a basic region on the surface of the molecule and has as ligands the main-chain amide of Arg-120 and the side chains of Asn-27, Arg-120, and Lys-125. This is suggested as the presumed binding site for heparin. Residues 106-115, which are presumed to bind to the bFGF receptor [Baird, A., Schubert, D., Ling, N. & Guillemin, R. (1988) Proc. Natl. Acad. Sci. USA 85, 2324-2328], include an irregular loop that extends somewhat from the surface of the protein and is about 25 angstrom from the presumed heparin binding site. The backbone structure of this putative receptor-binding loop is very similar, although not identical, to the corresponding region of interleukin 1-beta.