PDBsum entry 4grg

Immune system/inhibitor

PDB id: 4grg

Contents

Protein chains

124 a.a.

214 a.a.

PDB id:

4grg

Name:

Immune system/inhibitor

Title:

Crystal structure of ige complexed with e2_79, an anti-ige inhibitor

Structure:

Anti-ige inhibitor e2_79. Chain: a, b. Engineered: yes. Ig epsilon chain c region. Chain: c, d. Fragment: ig-like domains 3 and 4, residues 210-428. Engineered: yes. Mutation: yes

Source:

Escherichia coli. Organism_taxid: 562. Expressed in: escherichia coli. Expression_system_taxid: 562. Homo sapiens. Human. Organism_taxid: 9606. Gene: ighe. Expressed in: spodoptera frugiperda.

Resolution:

4.24Å R-factor: 0.273 R-free: 0.338

Authors:

B.Kim,T.S.Jardetzky

Key ref:

B.Kim et al. (2012). Accelerated disassembly of IgE-receptor complexes by a disruptive macromolecular inhibitor. Nature, 491, 613-617. PubMed id: 23103871

Date:

24-Aug-12 Release date: 12-Dec-12

Protein chains

No UniProt id for this chain

Struc: 124 a.a.

Protein chains

P01854  (IGHE_HUMAN) -  Immunoglobulin heavy constant epsilon from Homo sapiens

Seq: 546 a.a.

Struc: 214 a.a.*

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

Nature 491:613-617 (2012)

PubMed id: 23103871

Accelerated disassembly of IgE-receptor complexes by a disruptive macromolecular inhibitor.

B.Kim, A.Eggel, S.S.Tarchevskaya, M.Vogel, H.Prinz, T.S.Jardetzky.

ABSTRACT

IgE antibodies bind the high-affinity IgE Fc receptor (FcεRI), found primarily on mast cells and basophils, and trigger inflammatory cascades of the allergic response. Inhibitors of IgE-FcεRI binding have been identified and an anti-IgE therapeutic antibody (omalizumab) is used to treat severe allergic asthma. However, preformed IgE-FcεRI complexes that prime cells before allergen exposure dissociate extremely slowly and cannot be disrupted by strictly competitive inhibitors. IgE-Fc conformational flexibility indicated that inhibition could be mediated by allosteric or other non-classical mechanisms. Here we demonstrate that an engineered protein inhibitor, DARPin E2_79 (refs 9, 10, 11), acts through a non-classical inhibition mechanism, not only blocking IgE-FcεRI interactions, but actively stimulating the dissociation of preformed ligand-receptor complexes. The structure of the E2_79-IgE-Fc(3-4) complex predicts the presence of two non-equivalent E2_79 sites in the asymmetric IgE-FcεRI complex, with site 1 distant from the receptor and site 2 exhibiting partial steric overlap. Although the structure is indicative of an allosteric inhibition mechanism, mutational studies and quantitative kinetic modelling indicate that E2_79 acts through a facilitated dissociation mechanism at site 2 alone. These results demonstrate that high-affinity IgE-FcεRI complexes can be actively dissociated to block the allergic response and suggest that protein-protein complexes may be more generally amenable to active disruption by macromolecular inhibitors.