8Y9B

TcdB1 in complex with mini-binder

Summary for 8Y9B

• Entry DOI: 10.2210/pdb8y9b/pdb
• EMDB information: 39072
• Descriptor: Toxin B, De novo design mini-binder, ZINC ION (3 entities in total)
• Functional Keywords: mini-binder against c.difficle infection, toxin-de novo protein complex, toxin/de novo protein
• Biological source: Clostridioides difficile; More
• Total number of polymer chains: 2
• Total formula weight: 278270.15

Authors

Lv, X.C.,Lu, P.L. (deposition date: 2024-02-06, release date: 2024-08-28, Last modification date: 2024-10-16)

Primary citation

Lv, X.,Zhang, Y.,Sun, K.,Yang, Q.,Luo, J.,Tao, L.,Lu, P.
De novo design of mini-protein binders broadly neutralizing Clostridioides difficile toxin B variants.
Nat Commun, 15:8521-8521, 2024

PubMed Abstract: Clostridioides difficile toxin B (TcdB) is the key virulence factor accounting for C. difficile infection-associated symptoms. Effectively neutralizing different TcdB variants with a universal solution poses a significant challenge. Here we present the de novo design and characterization of pan-specific mini-protein binders against major TcdB subtypes. Our design successfully binds to the first receptor binding interface (RBI-1) of the varied TcdB subtypes, exhibiting affinities ranging from 20 pM to 10 nM. The cryo-electron microscopy (cryo-EM) structures of the mini protein binder in complex with TcdB1 and TcdB4 are consistent with the computational design models. The engineered and evolved variants of the mini-protein binder and chondroitin sulfate proteoglycan 4 (CSPG4), another natural receptor that binds to the second RBI (RBI-2) of TcdB, better neutralize major TcdB variants both in cells and in vivo, as demonstrated by the colon-loop assay using female mice. Our findings provide valuable starting points for the development of therapeutics targeting C. difficile infections (CDI).

PubMed: 39358329
DOI: 10.1038/s41467-024-52582-1

Experimental method

ELECTRON MICROSCOPY (3.2 Å)