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PDBsum entry 4gls
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Growth factor/inhibitor
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PDB id
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4gls
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Contents |
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95 a.a.
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56 a.a.
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56 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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Chemical synthesis and X-Ray structure of a heterochiral {d-Protein antagonist plus vascular endothelial growth factor} protein complex by racemic crystallography.
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Authors
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K.Mandal,
M.Uppalapati,
D.Ault-Riché,
J.Kenney,
J.Lowitz,
S.S.Sidhu,
S.B.Kent.
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Ref.
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Proc Natl Acad Sci U S A, 2012,
109,
14779-14784.
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PubMed id
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Abstract
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Total chemical synthesis was used to prepare the mirror image (D-protein) form
of the angiogenic protein vascular endothelial growth factor (VEGF-A). Phage
display against D-VEGF-A was used to screen designed libraries based on a unique
small protein scaffold in order to identify a high affinity ligand. Chemically
synthesized D- and L- forms of the protein ligand showed reciprocal chiral
specificity in surface plasmon resonance binding experiments: The L-protein
ligand bound only to D-VEGF-A, whereas the D-protein ligand bound only to
L-VEGF-A. The D-protein ligand, but not the L-protein ligand, inhibited the
binding of natural VEGF(165) to the VEGFR1 receptor. Racemic protein
crystallography was used to determine the high resolution X-ray structure of the
heterochiral complex consisting of {D-protein antagonist + L-protein form of
VEGF-A}. Crystallization of a racemic mixture of these synthetic proteins in
appropriate stoichiometry gave a racemic protein complex of more than 73 kDa
containing six synthetic protein molecules. The structure of the complex was
determined to a resolution of 1.6 Å. Detailed analysis of the interaction
between the D-protein antagonist and the VEGF-A protein molecule showed that the
binding interface comprised a contact surface area of approximately 800 Å(2)
in accord with our design objectives, and that the D-protein antagonist binds to
the same region of VEGF-A that interacts with VEGFR1-domain 2.
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