8URO

Crystal structure of IgG1-Fc fragment (E382S) in complex with Corynebacterial ENGase CU43 (D187A-E189A)

Summary for 8URO

• Entry DOI: 10.2210/pdb8uro/pdb
• Descriptor: Corynebacterial protease CP40, Immunoglobulin gamma-1 heavy chain (2 entities in total)
• Functional Keywords: igg1-fc, cu43, endoglycosidase, igg-specific, immune system
• Biological source: Corynebacterium ulcerans; More
• Total number of polymer chains: 6
• Total formula weight: 196552.82

Authors

Sastre, D.E.,Sultana, N.,Sundberg, E.J. (deposition date: 2023-10-26, release date: 2024-10-30, Last modification date: 2026-02-11)

Primary citation

Sastre, D.E.,Bournazos, S.,Huliciak, M.,Grace, B.A.C.,Boder, E.J.,Du, J.,Sultana, N.,Azzam, T.,Brown, T.J.,Flowers, M.W.,Lollar, P.,Xu, T.,Chernova, T.A.,Keith, A.D.,Keen, M.,Saltzman, A.,Martinez Gascuena, A.,Trastoy, B.,Guerin, M.E.,Frank, F.,Ortlund, E.A.,Ravetch, J.V.,Sundberg, E.J.
The mechanistic basis for interprotomer deglycosylation of antibodies by corynebacterial IgG-specific endoglycosidases.
Nat Commun, 16:6147-6147, 2025

PubMed Abstract: Corynebacterium diphtheriae clade species secrete single-domain endo-β-N-acetylglucosaminidases (ENGases) that specifically bind to human IgG antibodies and hydrolyze their N297-linked glycans. Here, we define the molecular mechanisms of IgG-specific deglycosylation for the entire family of corynebacterial IgG-specific ENGases, including but not limited to CU43 and CM49. By solving the crystal structure of CU43 in a 1:1 complex with the IgG1 Fc region, combined with targeted and saturation mutagenesis analysis and activity measurements using engineered antibodies, we establish an inter-protomeric mechanism of recognition and deglycosylation of IgG antibodies. Using in silico modeling, small-angle X-ray scattering and saturation mutagenesis we determine that CM49 uses a unique binding site on the Fc region, to process N297-linked glycans. Moreover, we demonstrate that CU43 treatment is highly effective in abrogating Fc effector functions in humanized mouse models, while preserving the neutralizing capacity of anti-influenza IgG antibodies, thereby conferring protection against lethal influenza challenge.

PubMed: 40610417
DOI: 10.1038/s41467-025-60986-w

Experimental method

X-RAY DIFFRACTION (3.62 Å)