High resolution mapping of the binding site on human IgG1 for Fc gamma RI, Fc gamma RII, Fc gamma RIII, and FcRn and design of IgG1 variants with improved binding to the Fc gamma R.


Abstract

Immunoglobulin G (IgG) Fc receptors play a critical role in linking IgG antibody-mediated immune responses with cellular effector functions. A high resolution map of the binding site on human IgG1 for human Fc gamma RI, Fc gamma RIIA, Fc gamma RIIB, Fc gamma RIIIA, and FcRn receptors has been determined. A common set of IgG1 residues is involved in binding to all Fc gamma R; Fc gamma RII and Fc gamma RIII also utilize residues outside this common set. In addition to residues which, when altered, abrogated binding to one or more of the receptors, several residues were found that improved binding only to specific receptors or simultaneously improved binding to one type of receptor and reduced binding to another type. Select IgG1 variants with improved binding to Fc gamma RIIIA exhibited up to 100% enhancement in antibody-dependent cell cytotoxicity using human effector cells; these variants included changes at residues not found at the binding interface in the IgG/Fc gamma RIIIA co-crystal structure (Sondermann, P., Huber, R., Oosthuizen, V., and Jacob, U. (2000) Nature 406, 267-273). These engineered antibodies may have important implications for improving antibody therapeutic efficacy.

Submission Details

ID: PpQa5ft44

Submitter: Shu-Ching Ou

Submission Date: Oct. 23, 2018, 6:04 p.m.

Version: 1

Publication Details
Shields RL;Namenuk AK;Hong K;Meng YG;Rae J;Briggs J;Xie D;Lai J;Stadlen A;Li B;Fox JA;Presta LG,J Biol Chem (2001) High resolution mapping of the binding site on human IgG1 for Fc gamma RI, Fc gamma RII, Fc gamma RIII, and FcRn and design of IgG1 variants with improved binding to the Fc gamma R. PMID:11096108
Additional Information

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P
 

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)


Relevant PDB Entries

Structure ID Release Date Resolution Structure Title
4HAF 2012-09-26T00:00:00+0000 2.04 Crystal structure of fc-fragment of human IgG2 antibody (primitive crystal form)
4HAG 2012-09-26T00:00:00+0000 3.4 Crystal structure of fc-fragment of human IgG2 antibody (centered crystal form)
4L4J 2013-06-07T00:00:00+0000 1.92 Crystal structure of fc-fragment of human IgG2-Sigma antibody
7LUS 2021-02-23T00:00:00+0000 2.45 IgG2 Fc Charge Pair Mutation version 1 (CPMv1)
7LUS 2021-02-23T00:00:00+0000 2.45 IgG2 Fc Charge Pair Mutation version 1 (CPMv1)
1ADQ 1997-02-18T00:00:00+0000 3.15 CRYSTAL STRUCTURE OF A HUMAN IGM RHEUMATOID FACTOR FAB IN COMPLEX WITH ITS AUTOANTIGEN IGG FC
1BBJ 1992-04-30T00:00:00+0000 3.1 CRYSTAL STRUCTURE OF A CHIMERIC FAB' FRAGMENT OF AN ANTIBODY BINDING TUMOUR CELLS
3EO1 2008-09-26T00:00:00+0000 3.1 Structure of the Fab Fragment of GC-1008 in Complex with Transforming Growth Factor-Beta 3
4B53 2012-08-02T00:00:00+0000 1.8 Crystal structure of the isolated IgG4 CH3 domain
4C54 2013-09-10T00:00:00+0000 1.9 Crystal structure of recombinant human IgG4 Fc

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
100.0 Immunoglobulin heavy constant gamma 1 P0DOX5 IGG1_HUMAN
100.0 Immunoglobulin heavy constant gamma 1 P01857 IGHG1_HUMAN
90.9 Immunoglobulin heavy constant gamma 1 P01859 IGHG2_HUMAN
90.9 Immunoglobulin heavy constant gamma 1 P01861 IGHG4_HUMAN