THE CRYSTAL-STRUCTURE OF A FAB FRAGMENT TO THE MELANOMA-ASSOCIATED GD2 GANGLIOSIDE

The GD2 ganglioside is a cell-surface component that appears on the su rface of metastatic melanoma cells and is a marker for the progression of the disease. The ME36.1 monoclonal antibody binds to the GD2 gangl ioside and has shown potential as a therapeutic antibody. ME36.1 is a possible alternative therapy to radiation, which is often ineffective in late-stage melanoma. The crystal structure of the Fab fragment of M E36.1 has been determined using molecular replacement and refined to a n R factor of 20.4% at 2.8 Angstrom resolution. The model has good geo metry with root-mean-square deviations of 0.008 Angstrom from ideal bo nd lengths and 1.7 degrees from ideal bond angles. The crystal structu re of the ME36.1 Fab shows that its complementarity determining region forms a groove-shaped binding site rather than the pocket-type observ ed in other sugar binding Fabs. Molecular modeling has placed a four-r esidue sugar, representative of GD2, in the antigen binding site. The GD2 sugar moiety is stabilized by a network of hydrogen bonds that def ine the specificity of ME36.1 toward its antigen. (C) 1997 Academic Pr ess.