4KV5

scFv GC1009 in complex with TGF-beta1.

Summary for 4KV5

• Entry DOI: 10.2210/pdb4kv5/pdb
• Related: 3EO0 3EO1 4KXZ
• Descriptor: Transforming growth factor beta-1 proprotein, Single-chain variable fragment GC1009 (2 entities in total)
• Functional Keywords: cysteine knot, fab, tgf-beta receptor mimetic, tgf-beta, tgf-beta receptor, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 8
• Total formula weight: 157865.60

Authors

Wei, R.,Moulin, A.G.,Mathieu, M. (deposition date: 2013-05-22, release date: 2014-09-24, Last modification date: 2024-11-20)

Primary citation

Moulin, A.,Mathieu, M.,Lawrence, C.,Bigelow, R.,Levine, M.,Hamel, C.,Marquette, J.P.,Le Parc, J.,Loux, C.,Ferrari, P.,Capdevila, C.,Dumas, J.,Dumas, B.,Rak, A.,Bird, J.,Qiu, H.,Pan, C.Q.,Edmunds, T.,Wei, R.R.
Structures of a pan-specific antagonist antibody complexed to different isoforms of TGF beta reveal structural plasticity of antibody-antigen interactions.
Protein Sci., 23:1698-1707, 2014

PubMed Abstract: Various important biological pathways are modulated by TGFβ isoforms; as such they are potential targets for therapeutic intervention. Fresolimumab, also known as GC1008, is a pan-TGFβ neutralizing antibody that has been tested clinically for several indications including an ongoing trial for focal segmental glomerulosclerosis. The structure of the antigen-binding fragment of fresolimumab (GC1008 Fab) in complex with TGFβ3 has been reported previously, but the structural capacity of fresolimumab to accommodate tight interactions with TGFβ1 and TGFβ2 was insufficiently understood. We report the crystal structure of the single-chain variable fragment of fresolimumab (GC1008 scFv) in complex with target TGFβ1 to a resolution of 3.00 Å and the crystal structure of GC1008 Fab in complex with TGFβ2 to 2.83 Å. The structures provide further insight into the details of TGFβ recognition by fresolimumab, give a clear indication of the determinants of fresolimumab pan-specificity and provide potential starting points for the development of isoform-specific antibodies using a fresolimumab scaffold.

PubMed: 25209176
DOI: 10.1002/pro.2548

Experimental method

X-RAY DIFFRACTION (3 Å)