PDBsum entry 3wn5

Immune system

PDB id: 3wn5

Contents

Protein chains

212 a.a.

210 a.a.

169 a.a.

Ligands

NAG-NAG-BMA-MAN-NAG-GAL-MAN-NAG-FUL ×3

NAG-NAG-BMA-MAN-MAN

NAG-NAG ×2

NAG-NAG-BMA-MAN-NAG-MAN-NAG-FUL

NAG

Metals

IOD ×16

Waters ×41

PDB id:

3wn5

Name:

Immune system

Title:

Crystal structure of asymmetrically engineered fc variant in complex with fcgriiia

Structure:

Ig gamma-1 chain c region. Chain: a, d. Fragment: unp residues 99-328. Engineered: yes. Mutation: yes. Ig gamma-1 chain c region. Chain: b, e. Fragment: unp residues 99-328. Engineered: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ighg1. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: hek293f. Gene: fcgr3a, cd16a, fcg3, fcgr3, igfr3. Expression_system_cell_line: hek293f

Resolution:

2.78Å R-factor: 0.238 R-free: 0.274

Authors:

S.Kadono,F.Mimoto,H.Katada,T.Igawa,T.Kamikawa,K.Hattori

Key ref:

F.Mimoto et al. (2014). Crystal structure of a novel asymmetrically engineered Fc variant with improved affinity for FcγRs. Mol Immunol, 58, 132-138. PubMed id: 24334029 DOI: 10.1016/j.molimm.2013.11.017

Date:

05-Dec-13 Release date: 19-Nov-14

Protein chains

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

Seq: 399 a.a.

Struc: 212 a.a.*

Protein chains

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

Seq: 399 a.a.

Struc: 210 a.a.*

Protein chains

P08637  (FCG3A_HUMAN) -  Low affinity immunoglobulin gamma Fc region receptor III-A from Homo sapiens

Seq: 254 a.a.

Struc: 169 a.a.*

* PDB and UniProt seqs differ at 20 residue positions (black crosses)

DOI no: 10.1016/j.molimm.2013.11.017

Mol Immunol 58:132-138 (2014)

PubMed id: 24334029

Crystal structure of a novel asymmetrically engineered Fc variant with improved affinity for FcγRs.

F.Mimoto, S.Kadono, H.Katada, T.Igawa, T.Kamikawa, K.Hattori.

ABSTRACT

Enhancing the effector function by optimizing the interaction between Fc and Fcγ receptor (FcγR) is a promising approach to enhance the potency of anticancer monoclonal antibodies (mAbs). To date, a variety of Fc engineering approaches to modulate the interaction have been reported, such as afucosylation in the heavy chain Fc region or symmetrically introducing amino acid substitutions into the region, and there is still room to improve FcγR binding and thermal stability of the CH2 domain with these approaches. Recently, we have reported that asymmetric Fc engineering, which introduces different substitutions into each Fc region of heavy chain, can further improve the FcγR binding while maintaining the thermal stability of the CH2 domain by fine-tuning the asymmetric interface between the Fc domain and FcγR. However, the structural mechanism by which the asymmetrically engineered Fc improved FcγR binding remained unclear. In order to elucidate the mechanism, we solved the crystal structure of a novel asymmetrically engineered Fc, asym-mAb23, in complex with FcγRIIIa. Asym-mAb23 has enhanced binding affinity for both FcγRIIIa and FcγRIIa at the highest level of previously reported Fc variants. The structural analysis reveals the features of the asymmetrically engineered Fc in comparison with symmetric Fc and how each asymmetrically introduced substitution contributes to the improved interaction between asym-mAb23 and FcγRIIIa. This crystal structure could be utilized to enable us to design a more potent asymmetric Fc.