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PDBsum entry 1i1c
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Immune system PDB id
1i1c

 

 

 

 

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Contents
Protein chains
205 a.a. *
Ligands
NAG-NAG-BMA-MAN-
NAG-MAN-NAG-FUL
NAG-NAG-BMA-MAN-
NAG-MAN-NAG-FUC
* Residue conservation analysis
PDB id:
1i1c
Name: Immune system
Title: Non-fcrn binding fc fragment of rat igg2a
Structure: Ig gamma-2a chain c region. Chain: a, b. Fragment: fc fragment. Synonym: igg2a. Engineered: yes. Mutation: yes
Source: Rattus norvegicus. Norway rat. Organism_taxid: 10116. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_organ: ovary.
Biol. unit: Dimer (from PQS)
Resolution:
2.70Å     R-factor:   0.241     R-free:   0.279
Authors: W.L.Martin,A.P.West Jr.,L.Gan,P.J.Bjorkman
Key ref:
W.L.Martin et al. (2001). Crystal structure at 2.8 A of an FcRn/heterodimeric Fc complex: mechanism of pH-dependent binding. Mol Cell, 7, 867-877. PubMed id: 11336709 DOI: 10.1016/S1097-2765(01)00230-1
Date:
31-Jan-01     Release date:   14-Feb-01    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
P20760  (IGG2A_RAT) -  Ig gamma-2A chain C region from Rattus norvegicus
Seq:
Struc: 		322 a.a.
205 a.a.*
Key:    Secondary structure  CATH domain
* PDB and UniProt seqs differ at 6 residue positions (black crosses)

 

 
DOI no: 10.1016/S1097-2765(01)00230-1 Mol Cell 7:867-877 (2001)
PubMed id: 11336709  
 
 
Crystal structure at 2.8 A of an FcRn/heterodimeric Fc complex: mechanism of pH-dependent binding.
W.L.Martin, A.P.West, L.Gan, P.J.Bjorkman.
 
  ABSTRACT  
 
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.
 
  Selected figure(s)  
 
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) 		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
 
  The above figures are reprinted by permission from Cell Press: Mol Cell (2001, 7, 867-877) copyright 2001.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20217455 A.Sesarman, G.Vidarsson, and C.Sitaru (2010).
The neonatal Fc receptor as therapeutic target in IgG-mediated autoimmune diseases.
  Cell Mol Life Sci, 67, 2533-2550.  
20171874 D.B.Tesar, and P.J.Björkman (2010).
An intracellular traffic jam: Fc receptor-mediated transport of immunoglobulin G.
  Curr Opin Struct Biol, 20, 226-233.  
20848168 D.C.Roopenian, and V.Z.Sun (2010).
Clinical ramifications of the MHC family Fc receptor FcRn.
  J Clin Immunol, 30, 790-797.  
20080725 S.T.Jung, S.T.Reddy, T.H.Kang, M.J.Borrok, I.Sandlie, P.W.Tucker, and G.Georgiou (2010).
Aglycosylated IgG variants expressed in bacteria that selectively bind FcgammaRI potentiate tumor cell killing by monocyte-dendritic cells.
  Proc Natl Acad Sci U S A, 107, 604-609.  
20802234 V.E.Kenanova, T.Olafsen, F.B.Salazar, L.E.Williams, S.Knowles, and A.M.Wu (2010).
Tuning the serum persistence of human serum albumin domain III:diabody fusion proteins.
  Protein Eng Des Sel, 23, 789-798.  
  20046570 D.S.Dimitrov (2009).
Engineered CH2 domains (nanoantibodies).
  MAbs, 1, 26-28.  
19165723 H.Pan, K.Chen, L.Chu, F.Kinderman, I.Apostol, and G.Huang (2009).
Methionine oxidation in human IgG2 Fc decreases binding affinities to protein A and FcRn.
  Protein Sci, 18, 424-433.  
19269963 H.Watanabe, H.Matsumaru, A.Ooishi, Y.Feng, T.Odahara, K.Suto, and S.Honda (2009).
Optimizing pH Response of Affinity between Protein G and IgG Fc: HOW ELECTROSTATIC MODULATIONS AFFECT PROTEIN-PROTEIN INTERACTIONS.
  J Biol Chem, 284, 12373-12383.
PDB codes: 2zw0 2zw1
19048248 J.E.Butler, N.Wertz, N.Deschacht, and I.Kacskovics (2009).
Porcine IgG: structure, genetics, and evolution.
  Immunogenetics, 61, 209-230.  
19495758 K.Baker, S.W.Qiao, T.Kuo, K.Kobayashi, M.Yoshida, W.I.Lencer, and R.S.Blumberg (2009).
Immune and non-immune functions of the (not so) neonatal Fc receptor, FcRn.
  Semin Immunopathol, 31, 223-236.  
19489651 R.E.Kontermann (2009).
Strategies to extend plasma half-lives of recombinant antibodies.
  BioDrugs, 23, 93.  
19164298 T.T.Kuo, E.J.de Muinck, S.M.Claypool, M.Yoshida, T.Nagaishi, V.G.Aveson, W.I.Lencer, and R.S.Blumberg (2009).
N-Glycan Moieties in Neonatal Fc Receptor Determine Steady-state Membrane Distribution and Directional Transport of IgG.
  J Biol Chem, 284, 8292-8300.  
  19460172 Y.He, G.J.Jensen, and P.J.Bjorkman (2009).
Nanogold as a specific marker for electron cryotomography.
  Microsc Microanal, 15, 183-188.  
18420815 A.H.Keeble, Z.Khan, A.Forster, and L.C.James (2008).
TRIM21 is an IgG receptor that is structurally, thermodynamically, and kinetically conserved.
  Proc Natl Acad Sci U S A, 105, 6045-6050.
PDB codes: 2vok 2vol 3zo0
18256279 D.B.Tesar, E.J.Cheung, and P.J.Bjorkman (2008).
The Chicken Yolk Sac IgY Receptor, a Mammalian Mannose Receptor Family Member, Transcytoses IgY across Polarized Epithelial Cells.
  Mol Biol Cell, 19, 1587-1593.  
18216124 E.R.Sprague, H.Reinhard, E.J.Cheung, A.H.Farley, R.D.Trujillo, H.Hengel, and P.J.Bjorkman (2008).
The human cytomegalovirus Fc receptor gp68 binds the Fc CH2-CH3 interface of immunoglobulin G.
  J Virol, 82, 3490-3499.  
18064051 F.Nimmerjahn, and J.V.Ravetch (2008).
Fcgamma receptors as regulators of immune responses.
  Nat Rev Immunol, 8, 34-47.  
18536555 P.J.Carter, and P.D.Senter (2008).
Antibody-drug conjugates for cancer therapy.
  Cancer J, 14, 154-169.  
18931413 P.Prabakaran, B.K.Vu, J.Gan, Y.Feng, D.S.Dimitrov, and X.Ji (2008).
Structure of an isolated unglycosylated antibody C(H)2 domain.
  Acta Crystallogr D Biol Crystallogr, 64, 1062-1067.
PDB code: 3dj9
18441054 S.Miyakawa, Y.Nomura, T.Sakamoto, Y.Yamaguchi, K.Kato, S.Yamazaki, and Y.Nakamura (2008).
Structural and molecular basis for hyperspecificity of RNA aptamer to human immunoglobulin G.
  RNA, 14, 1154-1163.  
  19017944 W.Mi, S.Wanjie, S.T.Lo, Z.Gan, B.Pickl-Herk, R.J.Ober, and E.S.Ward (2008).
Targeting the neonatal fc receptor for antigen delivery using engineered fc fragments.
  J Immunol, 181, 7550-7561.  
18363992 X.Y.Liu, L.M.Pop, and E.S.Vitetta (2008).
Engineering therapeutic monoclonal antibodies.
  Immunol Rev, 222, 9.  
17135257 A.Datta-Mannan, D.R.Witcher, Y.Tang, J.Watkins, and V.J.Wroblewski (2007).
Monoclonal antibody clearance. Impact of modulating the interaction of IgG with the neonatal Fc receptor.
  J Biol Chem, 282, 1709-1717.  
17703228 D.C.Roopenian, and S.Akilesh (2007).
FcRn: the neonatal Fc receptor comes of age.
  Nat Rev Immunol, 7, 715-725.  
17400754 L.C.James, A.H.Keeble, Z.Khan, D.A.Rhodes, and J.Trowsdale (2007).
Structural basis for PRYSPRY-mediated tripartite motif (TRIM) protein function.
  Proc Natl Acad Sci U S A, 104, 6200-6205.
PDB code: 2iwg
17315944 R.J.Boado, Y.Zhang, Y.Zhang, C.F.Xia, and W.M.Pardridge (2007).
Fusion antibody for Alzheimer's disease with bidirectional transport across the blood-brain barrier and abeta fibril disaggregation.
  Bioconjug Chem, 18, 447-455.  
17727329 R.Jefferis (2007).
Antibody therapeutics: isotype and glycoform selection.
  Expert Opin Biol Ther, 7, 1401-1413.  
17723309 W.He, C.Kivork, S.Machinani, M.K.Morphew, A.M.Gail, D.B.Tesar, N.E.Tiangco, J.R.McIntosh, and P.J.Bjorkman (2007).
A freeze substitution fixation-based gold enlarging technique for EM studies of endocytosed Nanogold-labeled molecules.
  J Struct Biol, 160, 103-113.  
16997417 A.J.Bitonti, and J.A.Dumont (2006).
Pulmonary administration of therapeutic proteins using an immunoglobulin transport pathway.
  Adv Drug Deliv Rev, 58, 1106-1118.  
17116867 C.Vaccaro, R.Bawdon, S.Wanjie, R.J.Ober, and E.S.Ward (2006).
Divergent activities of an engineered antibody in murine and human systems have implications for therapeutic antibodies.
  Proc Natl Acad Sci U S A, 103, 18709-18714.  
17004319 D.B.Tesar, N.E.Tiangco, and P.J.Bjorkman (2006).
Ligand valency affects transcytosis, recycling and intracellular trafficking mediated by the neonatal Fc receptor.
  Traffic, 7, 1127-1142.  
16646632 E.R.Sprague, C.Wang, D.Baker, and P.J.Bjorkman (2006).
Crystal structure of the HSV-1 Fc receptor bound to Fc reveals a mechanism for antibody bipolar bridging.
  PLoS Biol, 4, e148.
PDB codes: 2giy 2gj7
16619322 I.Gitlin, J.D.Carbeck, and G.M.Whitesides (2006).
Why are proteins charged? Networks of charge-charge interactions in proteins measured by charge ladders and capillary electrophoresis.
  Angew Chem Int Ed Engl, 45, 3022-3060.  
17048273 J.T.Andersen, J.Dee Qian, and I.Sandlie (2006).
The conserved histidine 166 residue of the human neonatal Fc receptor heavy chain is critical for the pH-dependent binding to albumin.
  Eur J Immunol, 36, 3044-3051.  
17487194 T.Olafsen, V.E.Kenanova, and A.M.Wu (2006).
Tunable pharmacokinetics: modifying the in vivo half-life of antibodies by directed mutagenesis of the Fc fragment.
  Nat Protoc, 1, 2048-2060.  
16370940 V.Kenanova, and A.M.Wu (2006).
Tailoring antibodies for radionuclide delivery.
  Expert Opin Drug Deliv, 3, 53-70.  
16793771 W.F.Dall'Acqua, P.A.Kiener, and H.Wu (2006).
Properties of human IgG1s engineered for enhanced binding to the neonatal Fc receptor (FcRn).
  J Biol Chem, 281, 23514-23524.  
15937987 A.Verdoliva, D.Marasco, A.De Capua, A.Saporito, P.Bellofiore, V.Manfredi, R.Fattorusso, C.Pedone, and M.Ruvo (2005).
A new ligand for immunoglobulin g subdomains by screening of a synthetic peptide library.
  Chembiochem, 6, 1242-1253.  
16186811 C.Vaccaro, J.Zhou, R.J.Ober, and E.S.Ward (2005).
Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels.
  Nat Biotechnol, 23, 1283-1288.  
16136591 D.T.Kamei, B.J.Lao, M.S.Ricci, R.Deshpande, H.Xu, B.Tidor, and D.A.Lauffenburger (2005).
Quantitative methods for developing Fc mutants with extended half-lives.
  Biotechnol Bioeng, 92, 748-760.  
16187338 D.Warnock, X.Bai, K.Autote, J.Gonzales, K.Kinealy, B.Yan, J.Qian, T.Stevenson, D.Zopf, and R.J.Bayer (2005).
In vitro galactosylation of human IgG at 1 kg scale using recombinant galactosyltransferase.
  Biotechnol Bioeng, 92, 831-842.  
16181004 J.A.Dumont, A.J.Bitonti, D.Clark, S.Evans, M.Pickford, and S.P.Newman (2005).
Delivery of an erythropoietin-Fc fusion protein by inhalation in humans through an immunoglobulin transport pathway.
  J Aerosol Med, 18, 294-303.  
16048548 L.Shao, O.Kamalu, and L.Mayer (2005).
Non-classical MHC class I molecules on intestinal epithelial cells: mediators of mucosal crosstalk.
  Immunol Rev, 206, 160-176.  
15210944 A.J.Bitonti, J.A.Dumont, S.C.Low, R.T.Peters, K.E.Kropp, V.J.Palombella, J.M.Stattel, Y.Lu, C.A.Tan, J.J.Song, A.M.Garcia, N.E.Simister, G.M.Spiekermann, W.I.Lencer, and R.S.Blumberg (2004).
Pulmonary delivery of an erythropoietin Fc fusion protein in non-human primates through an immunoglobulin transport pathway.
  Proc Natl Acad Sci U S A, 101, 9763-9768.  
14734541 E.R.Sprague, W.L.Martin, and P.J.Bjorkman (2004).
pH dependence and stoichiometry of binding to the Fc region of IgG by the herpes simplex virus Fc receptor gE-gI.
  J Biol Chem, 279, 14184-14193.  
15040582 J.M.Woof, and D.R.Burton (2004).
Human antibody-Fc receptor interactions illuminated by crystal structures.
  Nat Rev Immunol, 4, 89-99.  
14610077 P.Maillard, J.P.Lavergne, S.Sibéril, G.Faure, F.Roohvand, S.Petres, J.L.Teillaud, and A.Budkowska (2004).
Fcgamma receptor-like activity of hepatitis C virus core protein.
  J Biol Chem, 279, 2430-2437.  
14699147 P.R.Hinton, M.G.Johlfs, J.M.Xiong, K.Hanestad, K.C.Ong, C.Bullock, S.Keller, M.T.Tang, J.Y.Tso, M.Vásquez, and N.Tsurushita (2004).
Engineered human IgG antibodies with longer serum half-lives in primates.
  J Biol Chem, 279, 6213-6216.  
15355509 R.Fuchs, and I.Ellinger (2004).
Endocytic and transcytotic processes in villous syncytiotrophoblast: role in nutrient transport to the human fetus.
  Traffic, 5, 725-738.  
12768205 A.B.Herr, E.R.Ballister, and P.J.Bjorkman (2003).
Insights into IgA-mediated immune responses from the crystal structures of human FcalphaRI and its complex with IgA1-Fc.
  Nature, 423, 614-620.
PDB codes: 1ovz 1ow0
12948783 L.Presta (2003).
Antibody engineering for therapeutics.
  Curr Opin Struct Biol, 13, 519-525.  
12122212 A.E.Prota, D.R.Sage, T.Stehle, and J.D.Fingeroth (2002).
The crystal structure of human CD21: Implications for Epstein-Barr virus and C3d binding.
  Proc Natl Acad Sci U S A, 99, 10641-10646.
PDB code: 1ly2
12423304 B.Mayer, A.Zolnai, L.V.Frenyó, V.Jancsik, Z.Szentirmay, L.Hammarström, and I.Kacskovics (2002).
Redistribution of the sheep neonatal Fc receptor in the mammary gland around the time of parturition in ewes and its localization in the small intestine of neonatal lambs.
  Immunology, 107, 288-296.  
11847107 T.S.Ramalingam, S.A.Detmer, W.L.Martin, and P.J.Bjorkman (2002).
IgG transcytosis and recycling by FcRn expressed in MDCK cells reveals ligand-induced redistribution.
  EMBO J, 21, 590-601.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.

 

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