PDBsum entry 3wjj

Immune system

PDB id: 3wjj

Contents

Protein chains

212 a.a.

164 a.a.

Ligands

NAG-NAG-BMA-MAN-NAG-GAL-MAN-NAG-FUL ×2

Waters ×130

PDB id:

3wjj

Name:

Immune system

Title:

Crystal structure of iib selective fc variant, fc(p238d), in complex with fcgriib

Structure:

Ig gamma-1 chain c region. Chain: a, b. Fragment: unp residues 99-328. Engineered: yes. Mutation: yes. Low affinity immunoglobulin gamma fc region receptor ii-b. Chain: c. Fragment: extracellular domain, unp residues 45-217. Synonym: igg fc receptor ii-b, cdw32, fc-gamma rii-b, fc-gamma-riib,

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ighg1. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: hek293f. Gene: cd32, fcg2, fcgr2b, fcgr2c, igfr2. Expression_system_cell_line: hek293f

Resolution:

2.60Å R-factor: 0.232 R-free: 0.272

Authors:

S.Kadono,F.Mimoto,H.Katada,T.Igawa,T.Kuramochi,M.Muraoka,Y.Wada, K.Haraya,T.Miyazaki,K.Hattori

Key ref:

F.Mimoto et al. (2013). Engineered antibody Fc variant with selectively enhanced FcγRIIb binding over both FcγRIIa(R131) and FcγRIIa(H131). Protein Eng Des Sel, 26, 589-598. PubMed id: 23744091 DOI: 10.1093/protein/gzt022

Date:

10-Oct-13 Release date: 13-Nov-13

Protein chains

P01857  (IGHG1_HUMAN) -  Immunoglobulin heavy constant gamma 1 from Homo sapiens

Seq: 399 a.a.

Struc: 212 a.a.*

Protein chain

P31994  (FCG2B_HUMAN) -  Low affinity immunoglobulin gamma Fc region receptor II-b from Homo sapiens

Seq: 310 a.a.

Struc: 164 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

DOI no: 10.1093/protein/gzt022

Protein Eng Des Sel 26:589-598 (2013)

PubMed id: 23744091

Engineered antibody Fc variant with selectively enhanced FcγRIIb binding over both FcγRIIa(R131) and FcγRIIa(H131).

F.Mimoto, H.Katada, S.Kadono, T.Igawa, T.Kuramochi, M.Muraoka, Y.Wada, K.Haraya, T.Miyazaki, K.Hattori.

ABSTRACT

Engaging inhibitory FcγRIIb by Fc region has been recently reported to be an attractive approach for improving the efficacy of antibody therapeutics. However, the previously reported S267E/L328F variant with enhanced binding affinity to FcγRIIb, also enhances binding affinity to FcγRIIa(R131) allotype to a similar degree because FcγRIIb and FcγRIIa(R131) are structurally similar. In this study, we applied comprehensive mutagenesis and structure-guided design based on the crystal structure of the Fc/FcγRIIb complex to identify a novel Fc variant with selectively enhanced FcγRIIb binding over both FcγRIIa(R131) and FcγRIIa(H131). This novel variant has more than 200-fold stronger binding affinity to FcγRIIb than wild-type IgG1, while binding affinity to FcγRIIa(R131) and FcγRIIa(H131) is comparable with or lower than wild-type IgG1. This selectivity was achieved by conformational change of the C(H)2 domain by mutating Pro to Asp at position 238. Fc variant with increased binding to both FcγRIIb and FcγRIIa induced platelet aggregation and activation in an immune complex form in vitro while our novel variant did not. When applied to agonistic anti-CD137 IgG1 antibody, our variant greatly enhanced the agonistic activity. Thus, the selective enhancement of FcγRIIb binding achieved by our Fc variant provides a novel tool for improving the efficacy of antibody therapeutics.