VEGF IN COMPLEX WITH A NEUTRALIZING ANTIBODY

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Human VEGF receptor binding domain (dark olive, purple) complex with antibody (aqua, blue, red, rust) (PDB code 1bj1)

Publication Abstract from PubMed

BACKGROUND: Vascular endothelial growth factor (VEGF) is a highly specific angiogenic growth factor; anti-angiogenic treatment through inhibition of receptor activation by VEGF might have important therapeutic applications in diseases such as diabetic retinopathy and cancer. A neutralizing anti-VEGF antibody shown to suppress tumor growth in an in vivo murine model has been used as the basis for production of a humanized version. RESULTS: We present the crystal structure of the complex between VEGF and the Fab fragment of this humanized antibody, as well as a comprehensive alanine-scanning analysis of the contact residues on both sides of the interface. Although the VEGF residues critical for antibody binding are distinct from those important for high-affinity receptor binding, they occupy a common region on VEGF, demonstrating that the neutralizing effect of antibody binding results from steric blocking of VEGF-receptor interactions. Of the residues buried in the VEGF-Fab interface, only a small number are critical for high-affinity binding; the essential VEGF residues interact with those of the Fab fragment, generating a remarkable functional complementarity at the interface. CONCLUSIONS: Our findings suggest that the character of antigen-antibody interfaces is similar to that of other protein-protein interfaces, such as ligand-receptor interactions; in the case of VEGF, the principal difference is that the residues essential for binding to the Fab fragment are concentrated in one continuous segment of polypeptide chain, whereas those essential for binding to the receptor are distributed over four different segments and span across the dimer interface.

VEGF and the Fab fragment of a humanized neutralizing antibody: crystal structure of the complex at 2.4 A resolution and mutational analysis of the interface.,Muller YA, Chen Y, Christinger HW, Li B, Cunningham BC, Lowman HB, de Vos AM Structure. 1998 Sep 15;6(9):1153-67. PMID:9753694

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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References

  1. Muller YA, Chen Y, Christinger HW, Li B, Cunningham BC, Lowman HB, de Vos AM. VEGF and the Fab fragment of a humanized neutralizing antibody: crystal structure of the complex at 2.4 A resolution and mutational analysis of the interface. Structure. 1998 Sep 15;6(9):1153-67. PMID:9753694

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