7MFK

Structure of the Clostridium perfringens GH89 in complex with alpha-HNJNAc

Summary for 7MFK

• Entry DOI: 10.2210/pdb7mfk/pdb
• Descriptor: Alpha-N-acetylglucosaminidase family protein, 1,2-ETHANEDIOL, CALCIUM ION, ... (6 entities in total)
• Functional Keywords: naglu, clostridium perfringens, mps iiib, inhibitor, gh89, glycoside hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Clostridium perfringens (strain ATCC 13124 / DSM 756 / JCM 1290 / NCIMB 6125 / NCTC 8237 / Type A)
• Total number of polymer chains: 1
• Total formula weight: 104007.87

Authors

Boraston, A.B. (deposition date: 2021-04-09, release date: 2021-07-28, Last modification date: 2023-10-18)

Primary citation

Zhu, S.,Jagadeesh, Y.,Tran, A.T.,Imaeda, S.,Boraston, A.,Alonzi, D.S.,Poveda, A.,Zhang, Y.,Desire, J.,Charollais-Thoenig, J.,Demotz, S.,Kato, A.,Butters, T.D.,Jimenez-Barbero, J.,Sollogoub, M.,Bleriot, Y.
Iminosugar C-Glycosides Work as Pharmacological Chaperones of NAGLU, a Glycosidase Involved in MPS IIIB Rare Disease*.
Chemistry, 27:11291-11297, 2021

PubMed Abstract: Mucopolysaccharidosis type IIIB is a devastating neurological disease caused by a lack of the lysosomal enzyme, α-N-acetylglucosaminidase (NAGLU), leading to a toxic accumulation of heparan sulfate. Herein we explored a pharmacological chaperone approach to enhance the residual activity of NAGLU in patient fibroblasts. Capitalizing on the three-dimensional structures of two modest homoiminosugar-based NAGLU inhibitors in complex with bacterial homolog of NAGLU, CpGH89, we have synthesized a library of 17 iminosugar C-glycosides mimicking N-acetyl-D-glucosamine and bearing various pseudo-anomeric substituents of both α- and β-configuration. Elaboration of the aglycon moiety results in low micromolar selective inhibitors of human recombinant NAGLU, but surprisingly it is the non-functionalized and wrongly configured β-homoiminosugar that was proved to act as the most promising pharmacological chaperone, promoting a 2.4 fold activity enhancement of mutant NAGLU at its optimal concentration.

PubMed: 34106504
DOI: 10.1002/chem.202101408

Experimental method

X-RAY DIFFRACTION (2.13 Å)