3EO0

Structure of the Transforming Growth Factor-Beta Neutralizing Antibody GC-1008

Summary for 3EO0

• Entry DOI: 10.2210/pdb3eo0/pdb
• Related: 3EO1
• Descriptor: GC-1008 Fab Light Chain, GC-1008 Fab Heavy Chain, GLYCEROL, ... (4 entities in total)
• Functional Keywords: cytokine neutralizing antibody, fab fragment, immune system
• Biological source: Mus musculus; More
• Total number of polymer chains: 4
• Total formula weight: 95102.06

Authors

Gruetter, C.,Gruetter, M.G. (deposition date: 2008-09-26, release date: 2008-12-02, Last modification date: 2024-11-13)

Primary citation

Wilkinson, T.,Turner, R.,Podichetty, S.,Finch, D.,McCourt, M.,Loning, S.,Jermutus, L.
A cytokine-neutralizing antibody as a structural mimetic of 2 receptor interactions
Proc.Natl.Acad.Sci.Usa, 105:20251-20256, 2008

PubMed Abstract: TGF-beta isoforms are key modulators of a broad range of biological pathways and increasingly are exploited as therapeutic targets. Here, we describe the crystal structures of a pan-TGF-beta neutralizing antibody, GC-1008, alone and in complex with TGF-beta3. The antibody is currently in clinical evaluation for idiopathic pulmonary fibrosis, melanoma, and renal cell cancer. GC-1008 recognizes an asymmetric binding interface across the TGF-beta homodimer with high affinity. Whereas both cognate receptors, TGF-beta-receptor types I and II, are required to recognize all 3 TGF-beta isoforms, GC-1008 has been engineered to bind with high affinity to TGF-beta1, 2, and 3 via a single interaction surface. Comparison with existing structures and models of TGF-beta interaction with its receptors suggests that the antibody binds to a similar epitope to the 2 receptors together and is therefore a structurally different but functionally identical mimic of the binding mode of both receptors.

PubMed: 19073914
DOI: 10.1073/pnas.0807200106

Experimental method

X-RAY DIFFRACTION (1.75 Å)