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. 2010 Sep 3;285(36):27694-701.
doi: 10.1074/jbc.M110.120667. Epub 2010 Jun 30.

X-ray crystal structures of monomeric and dimeric peptide inhibitors in complex with the human neonatal Fc receptor, FcRn

Adam R Mezo  1 , Vandana Sridhar, John Badger, Paul Sakorafas, Vicki Nienaber
Affiliations

X-ray crystal structures of monomeric and dimeric peptide inhibitors in complex with the human neonatal Fc receptor, FcRn

Adam R Mezo et al. J Biol Chem. .

Abstract

The neonatal Fc receptor, FcRn, is responsible for the long half-life of IgG molecules in vivo and is a potential therapeutic target for the treatment of autoimmune diseases. A family of peptides comprising the consensus motif GHFGGXY, where X is preferably a hydrophobic amino acid, was shown previously to inhibit the human IgG:human FcRn protein-protein interaction (Mezo, A. R., McDonnell, K. A., Tan Hehir, C. A., Low, S. C., Palombella, V. J., Stattel, J. M., Kamphaus, G. D., Fraley, C., Zhang, Y., Dumont, J. A., and Bitonti, A. J. (2008) Proc. Natl. Acad. Sci. U.S.A., 105, 2337-2342). Herein, the x-ray crystal structure of a representative monomeric peptide in complex with human FcRn was solved to 2.6 A resolution. The structure shows that the peptide binds to human FcRn at the same general binding site as does the Fc domain of IgG. The data correlate well with structure-activity relationship data relating to how the peptide family binds to human FcRn. In addition, the x-ray crystal structure of a representative dimeric peptide in complex with human FcRn shows how the bivalent ligand can bridge two FcRn molecules, which may be relevant to the mechanism by which the dimeric peptides inhibit FcRn and increase IgG catabolism in vivo. Modeling of the peptide:FcRn structure as compared with available structural data on Fc and FcRn suggest that the His-6 and Phe-7 (peptide) partially mimic the interaction of His-310 and Ile-253 (Fc) in binding to FcRn, but using a different backbone topology.

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Figures

FIGURE 1.
FIGURE 1.
Sequence and primary structure of peptides 1–3. Solid lines between Pen and Cys amino acids denote a disulfide bond.
FIGURE 2.
FIGURE 2.
Comparison of the deg-shFcRn:peptide 1 structure and a model of human FcRn:Fc showing that the peptide and Fc occupy the same binding site. A, crystal structure of peptide 1 in complex with deg-shFcRn at 2.6 Å resolution depicting the binding location of peptide 1 on FcRn. B, model of the human FcRn:Fc complex obtained by overlaying a crystal structure of the human FcRn protein (this work) and the rat FcRn:Fc complex (PDB entry: 1I1A). For both figures, FcRn is depicted in cartoon form, and the peptide or Fc is represented by a purple and blue tube, respectively.
FIGURE 3.
FIGURE 3.
A, overlay of the main chain atoms of the crystal structure of peptide 1 (purple) in complex with deg-shFcRn (green) with the apo structure (PDB entry: 1EXU, blue). The loop region from amino acid 52–59 (red) was not seen in the apo crystal structure (1EXU) but is resolved in the crystal form containing peptide 1. B, close-up of the main chain atoms of the conformation of the loop region around Gly-84 from deg-shFcRn that is modified in response to peptide binding relative to the conformation seen in the apo structure. The peptide 1 side-chains of His-6 and Phe-7 are also shown. An ordered water molecule is bound between the amide proton from Gly-86 on deg-shFcRn and the amide carboxyl from Phe-7 on the peptide as shown by the dashed line.
FIGURE 4.
FIGURE 4.
Key amino acids responsible for the binding of peptide 1 (purple) to deg-shFcRn (yellow).
FIGURE 5.
FIGURE 5.
Overlay of peptide 1 with the docking model for the human FcRn:Fc complex. A, main chain bonds for the template structure (rat FcRn:Fc complex) (15) are colored yellow, the human FcRn protein with peptide 1 bound (this work) is shown with main chain bonds colored red, and the human Fc structure is shown with main chain bonds colored green. The main chain atoms from the peptide are shown in purple. The main chain traces for the human Fc and FcRn components align well with the rat FcRn:Fc complex in this region. B, close-up of all atom detail of the peptide in the region of His-6/Phe-7 with the aligned human Fc structure. Amino acids His-310 and Ile-253 are positioned so as to be approximately comparable to His-6 and Phe-7 but the main chain trace is different.
FIGURE 6.
FIGURE 6.
Crystal structure of peptide 3 in complex with deg-shFcRn to 3.3 Å resolution. The traces of the FcRn heavy chain is shown in red, the chain traces of the β2-microglobin domains is shown in blue, and the atomic model for peptide 3 is shown with bonds drawn in purple. The linker connecting the two peptide monomers, consisting of Arg-succinyl-Arg-Phe, is not visible in this structure due to inherent flexibility in this region and/or the limited resolution of the data.
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