5O4E

Crystal structure of VEGF in complex with heterodimeric Fcab JanusCT6

Summary for 5O4E

• Entry DOI: 10.2210/pdb5o4e/pdb
• Related: 5K64 5K65
• Descriptor: Immunoglobulin gamma-1 heavy chain, CACODYLATE ION, 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, ... (12 entities in total)
• Functional Keywords: antibody engineering, immunoglobulin g1, fc fragment, fcab, heterodimeric fcab, ch3 domain, vegf, vascular endothelial growth factor, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 130697.28

Authors

Mlynek, G.,Lobner, E.,Kubinger, K.,Humm, A.,Obinger, C.,Djinovic-Carugo, K. (deposition date: 2017-05-29, release date: 2017-08-30, Last modification date: 2024-10-16)

Primary citation

Lobner, E.,Humm, A.S.,Mlynek, G.,Kubinger, K.,Kitzmuller, M.,Traxlmayr, M.W.,Djinovic-Carugo, K.,Obinger, C.
Two-faced Fcab prevents polymerization with VEGF and reveals thermodynamics and the 2.15 angstrom crystal structure of the complex.
MAbs, 9:1088-1104, 2017

PubMed Abstract: Fcabs (Fc domain with antigen-binding sites) are promising novel therapeutics. By engineering of the C-terminal loops of the CH3 domains, 2 antigen binding sites can be inserted in close proximity. To elucidate the binding mode(s) between homodimeric Fcabs and small homodimeric antigens, the interaction between the Fcabs 448 and CT6 (having the AB, CD and EF loops and the C-termini engineered) with homodimeric VEGF was investigated. The crystal structures of these Fcabs, which form polymers with the antigen VEGF in solution, were determined. However, construction of heterodimeric Fcabs (JanusFcabs: one chain Fc-wt, one chain VEGF-binding) results in formation of distinct JanusFcab-VEGF complexes (2:1), which allowed elucidation of the crystal structure of the JanusCT6-VEGF complex at 2.15 Å resolution. VEGF binding to Janus448 and JanusCT6 is shown to be entropically unfavorable, but enthalpically favorable. Structure-function relationships are discussed with respect to Fcab design and engineering strategies.

PubMed: 28816592
DOI: 10.1080/19420862.2017.1364825

Experimental method

X-RAY DIFFRACTION (2.15 Å)