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 surface of metastatic melanoma cells and is a marker for the progression of the disease. The ME36.1 monoclonal antibody binds to the GD2 ganglioside 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 ME36.1 has been determined using molecular replacement and refined to an R factor of 20.4% at 2.8 A resolution. The model has good geometry with root-mean-square deviations of 0.008 A from ideal bond lengths and 1.7 degrees from ideal bond angles. The crystal structure of the ME36.1 Fab shows that its complementarity determining region forms a groove-shaped binding site rather than the pocket-type observed in other sugar binding Fabs. Molecular modeling has placed a four-residue sugar, representative of GD2, in the antigen binding site. The GD2 sugar moiety is stabilized by a network of hydrogen bonds that define the specificity of ME36.1 toward its antigen.
Pichla
S L
SL
Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
Murali
R
R
Burnett
R M
RM
D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000276:immunology; D001666:Binding Sites, Antibody; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D003460:Crystallization; D018360:Crystallography, X-Ray; D005732:Gangliosides / Q000737:chemistry / Q000276:immunology*; D006860:Hydrogen Bonding; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry* / Q000276:immunology; D007135:Immunoglobulin Variable Region; D008545:Melanoma / Q000737:chemistry* / Q000276:immunology / Q000628:therapy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011487:Protein Conformation; D012984:Software
D000911:Antibodies, Monoclonal; D005732:Gangliosides; D007140:Immunoglobulin Fab Fragments; D007135:Immunoglobulin Variable Region; C019403:ganglioside, GD2