7sht

From Proteopedia

Structure of a partially disrupted IgE high affinity receptor complex bound to an omalizumab variant

Structural highlights

7sht is a 7 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 7.29Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

FCERA_HUMAN Binds to the Fc region of immunoglobulins epsilon. High affinity receptor. Responsible for initiating the allergic response. Binding of allergen to receptor-bound IgE leads to cell activation and the release of mediators (such as histamine) responsible for the manifestations of allergy. The same receptor also induces the secretion of important lymphokines.

Publication Abstract from PubMed

Antibody drugs exert therapeutic effects via a range of mechanisms, including competitive inhibition, allosteric modulation, and immune effector mechanisms. Facilitated dissociation is an additional mechanism where antibody-mediated "disruption" of stable high-affinity macromolecular complexes can potentially enhance therapeutic efficacy. However, this mechanism is not well understood or utilized therapeutically. Here, we investigate and engineer the weak disruptive activity of an existing therapeutic antibody, omalizumab, which targets IgE antibodies to block the allergic response. We develop a yeast display approach to select for and engineer antibody disruptive efficiency and generate potent omalizumab variants that dissociate receptor-bound IgE. We determine a low resolution cryo-EM structure of a transient disruption intermediate containing the IgE-Fc, its partially dissociated receptor and an antibody inhibitor. Our results provide a conceptual framework for engineering disruptive inhibitors for other targets, insights into the failure in clinical trials of the previous high affinity omalizumab HAE variant and anti-IgE antibodies that safely and rapidly disarm allergic effector cells.

Directed evolution of and structural insights into antibody-mediated disruption of a stable receptor-ligand complex.,Pennington LF, Gasser P, Kleinboelting S, Zhang C, Skiniotis G, Eggel A, Jardetzky TS Nat Commun. 2021 Dec 3;12(1):7069. doi: 10.1038/s41467-021-27397-z. PMID:34862384^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Pennington LF, Gasser P, Kleinboelting S, Zhang C, Skiniotis G, Eggel A, Jardetzky TS. Directed evolution of and structural insights into antibody-mediated disruption of a stable receptor-ligand complex. Nat Commun. 2021 Dec 3;12(1):7069. PMID:34862384 doi:10.1038/s41467-021-27397-z