4TUJ: Crystal Structure Of Monoclonal Antibody Against Neuroblastoma Associated Antigen

Citation:
Abstract
Monoclonal antibodies targeting GD2 ganglioside (GD2) have recently been approved for the treatment of high risk neuroblastoma and are extensively evaluated in clinics in other indications. This study illustrates how a therapeutic antibody distinguishes between different types of gangliosides present on normal and cancer cells and informs how synthetic peptides can imitate ganglioside in its binding to the antibody. Using high resolution crystal structures we demonstrate that the ganglioside recognition by a model antibody (14G2a) is based primarily on an extended network of direct and water molecule mediated hydrogen bonds. Comparison of the GD2-Fab structure with that of a ligand free antibody reveals an induced fit mechanism of ligand binding. These conclusions are validated by directed mutagenesis and allowed structure guided generation of antibody variant with improved affinity toward GD2. Contrary to the carbohydrate, both evaluated mimetic peptides utilize a "key and lock" interaction mechanism complementing the surface of the antibody binding groove exactly as found in the empty structure. The interaction of both peptides with the Fab relies considerably on hydrophobic contacts however, the detailed connections differ significantly between the peptides. As such, the evaluated peptide carbohydrate mimicry is defined primarily in a functional and not in structural manner.
PDB ID: 4TUJDownload
MMDB ID: 130848
PDB Deposition Date: 2014/6/24
Updated in MMDB: 2015/11
Experimental Method:
x-ray diffraction
Resolution: 1.89  Å
Source Organism:
Mus musculus
Similar Structures:
Biological Unit for 4TUJ: trimeric; determined by software (PISA)
Molecular Components in 4TUJ
Label Count Molecule
Proteins (3 molecules)
1
Heavy Chain of Monoclonal Antibody Against Neuroblastoma Associated Antigen
Molecule annotation
1
Light Chain of Monoclonal Antibody Against Neuroblastoma Associated Antigen
Molecule annotation
1
Peptide1
Molecule annotation
* Click molecule labels to explore molecular sequence information.

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