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PDBsum entry 1i1c
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Immune system
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PDB id
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1i1c
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Crystal structure at 2.8 a of an fcrn/heterodimeric fc complex: mechanism of ph-Dependent binding.
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Authors
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W.L.Martin,
A.P.West,
L.Gan,
P.J.Bjorkman.
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Ref.
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Mol Cell, 2001,
7,
867-877.
[DOI no: ]
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PubMed id
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Abstract
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The neonatal Fc receptor (FcRn) transports immunoglobulin G (IgG) across
epithelia, binding IgG in acidic vesicles (pH < or = 6.5) and releasing IgG
in the blood at pH 7.4. Well-ordered FcRn/Fc crystals are prevented by the
formation of "oligomeric ribbons" of FcRn dimers bridged by Fc
homodimers, thus we crystallized a 1:1 complex between rat FcRn and a
heterodimeric Fc containing only one FcRn binding site. The 2.8 A complex
structure demonstrates that FcRn uses its alpha2 and beta2-microglobulin domains
and carbohydrate to interact with the Fc C(gamma)2-C(gamma)3 interface. The
structure reveals conformational changes in Fc and three titratable salt bridges
that confer pH-dependent binding, and can be used to guide rational design of
therapeutic IgGs with longer serum half-lives.
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Figure 1.
Figure 1. FcRn/Fc, FcRn/hdFc, and nbFc Structures(A)
FcRn/Fc complexes in the oligomeric ribbon observed in crystals
of FcRn bound to wtFc. FcRn/Fc crystals grown using human,
mouse, or rat FcRn and human, mouse, or rat Fc subclasses all
appear to contain the oligomeric ribbon packing in which FcRn
dimers are bridged by Fc homodimers. Such crystals diffract
aniostropically to 3.5 Å–8 Å, with the highest
resolution in the direction of the long axis of the FcRn
dimer.(B) Ribbon diagrams of the structures of FcRn/hdFc and
nbFc. Ordered N-linked carbohydrates are shown in ball-and-stick
representation. Disulfide bonds are yellow. Regions of disorder
in the distal C[γ]2 domain are shown as dashed lines. The
FcRn/hdFc complexes are packed in the crystals such that the
nbFc chain of the hdFc contacts an FcRn in an adjacent FcRn/hdFc
complex. This interaction involves a face of the FcRn α3 domain
opposite from the Fc binding site, and the buried surface area
(577 Å^2 total) is near the mean size buried in typical
crystal contacts (570 Å^2) (Janin, 1997), thus it is a
nonspecific interaction.(C) Close-up of the FcRn/hdFc interface.
Interface residues are turquoise (positively charged), pink
(negatively charged), and yellow (hydrophobic). The carbohydrate
attached to residue Asn-87 was omitted for clarity.(D) The
FcRn/hdFc model in the region of the N-linked carbohydrate
attached to FcRn Asn-128 superimposed on a 2.8 Å
SIGMAA-weighted 2F[o]-F[c] annealed omit electron density map
contoured at 1.0 σ.(E) Comparison of the Fc 251 to 256 loop in
the wt (red) and nb (gold) sides of hdFc (Cα rms deviation of
1.78 Å)
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Figure 3.
Figure 3. Positions that Affect Affinity for Human FcRn
Highlighted on the Structure of Human FcA single polypeptide
chain from the structure of human Fc (coordinates obtained from
Mark Ultsch, Genentech) is shown with side chains highlighting
positions where substitutions result in reduced (red side chain)
or enhanced (green side chain) affinity for human FcRn, based
upon mutagenesis studies by Shields et al. (2001) (Table 4).
Residues within the predicted interface with human FcRn (within
5 Å of an FcRn atom using a human FcRn/human Fc model
generated from the rat FcRn/hdFc structure) are indicated by
thick side chains and labels. Residues predicted to be outside
of the interface are indicated by thin side chains and smaller
labels
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The above figures are
reprinted
by permission from Cell Press:
Mol Cell
(2001,
7,
867-877)
copyright 2001.
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