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PDBsum entry 5o4e
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Immune system
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PDB id
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5o4e
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Contents |
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209 a.a.
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216 a.a.
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181 a.a.
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95 a.a.
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References listed in PDB file
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Key reference
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Title
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Two-Faced fcab prevents polymerization with vegf and reveals thermodynamics and the 2.15 å crystal structure of the complex.
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Authors
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E.Lobner,
A.S.Humm,
G.Mlynek,
K.Kubinger,
M.Kitzmüller,
M.W.Traxlmayr,
K.Djinović-Carugo,
C.Obinger.
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Ref.
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MAbs, 2017,
9,
1088-1104.
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PubMed id
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Abstract
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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.
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