8PE2

Crystal structure of Gel4 in complex with Nanobody 3

Summary for 8PE2

• Entry DOI: 10.2210/pdb8pe2/pdb
• Descriptor: 1,3-beta-glucanosyltransferase, Nanobody 3, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: transglycosylase, b-1, 3-glucan, nanobodies, fungal diseases, transferase
• Biological source: Aspergillus fumigatus; More
• Total number of polymer chains: 2
• Total formula weight: 64602.83

Authors

Macias-Leon, J.,Redrado-Hernandez, S.,Castro-Lopez, J.,Sanz, A.B.,Arias, M.,Farkas, V.,Vincke, C.,Muyldermans, S.,Pardo, J.,Arroyo, J.,Galvez, E.,Hurtado-Guerrero, R. (deposition date: 2023-06-13, release date: 2024-06-19, Last modification date: 2024-11-13)

Primary citation

Redrado-Hernandez, S.,Macias-Leon, J.,Castro-Lopez, J.,Belen Sanz, A.,Dolader, E.,Arias, M.,Gonzalez-Ramirez, A.M.,Sanchez-Navarro, D.,Petryk, Y.,Farkas, V.,Vincke, C.,Muyldermans, S.,Garcia-Barbazan, I.,Del Agua, C.,Zaragoza, O.,Arroyo, J.,Pardo, J.,Galvez, E.M.,Hurtado-Guerrero, R.
Broad Protection against Invasive Fungal Disease from a Nanobody Targeting the Active Site of Fungal beta-1,3-Glucanosyltransferases.
Angew.Chem.Int.Ed.Engl., 63:e202405823-e202405823, 2024

PubMed Abstract: Invasive fungal disease accounts for about 3.8 million deaths annually, an unacceptable rate that urgently prompts the discovery of new knowledge-driven treatments. We report the use of camelid single-domain nanobodies (Nbs) against fungal β-1,3-glucanosyltransferases (Gel) involved in β-1,3-glucan transglycosylation. Crystal structures of two Nbs with Gel4 from Aspergillus fumigatus revealed binding to a dissimilar CBM43 domain and a highly conserved catalytic domain across fungal species, respectively. Anti-Gel4 active site Nb3 showed significant antifungal efficacy in vitro and in vivo prophylactically and therapeutically against different A. fumigatus and Cryptococcus neoformans isolates, reducing the fungal burden and disease severity, thus significantly improving immunocompromised animal survival. Notably, C. deneoformans (serotype D) strains were more susceptible to Nb3 and genetic Gel deletion than C. neoformans (serotype A) strains, indicating a key role for β-1,3-glucan remodelling in C. deneoformans survival. These findings add new insight about the role of β-1,3-glucan in fungal biology and demonstrate the potential of nanobodies in targeting fungal enzymes to combat invasive fungal diseases.

PubMed: 38856634
DOI: 10.1002/anie.202405823

Experimental method

X-RAY DIFFRACTION (2.05 Å)