8RW3

Crystal Structure of Agd31B, alpha-transglucosylase, complexed with a non-covalent 1,2- Cyclophellitol aziridine

Summary for 8RW3

• Entry DOI: 10.2210/pdb8rw3/pdb
• Descriptor: Oligosaccharide 4-alpha-D-glucosyltransferase, (1~{S},2~{R},3~{R},4~{R},6~{S})-4-(hydroxymethyl)-7-azabicyclo[4.1.0]heptane-2,3-diol, OXALATE ION, ... (7 entities in total)
• Functional Keywords: glycoside hydrolase, structural protein
• Biological source: Cellvibrio japonicus Ueda107
• Total number of polymer chains: 3
• Total formula weight: 280197.74

Authors

Moran, E.,Davies, G.,Ofamn, T.,Heming, J.,Nin-Hill, A.,Kullmer, F.,Steneker, R.,Klein, A.,Bennett, M.,Ruijgrok, G.,Kok, K.,Aerts, J.,Van der Marel, G.,Rovira, C.,Artola, M.,Codee, J.,Overkleeft, H. (deposition date: 2024-02-02, release date: 2024-05-15, Last modification date: 2024-11-06)

Primary citation

Ofman, T.P.,Heming, J.J.A.,Nin-Hill, A.,Kullmer, F.,Moran, E.,Bennett, M.,Steneker, R.,Klein, A.M.,Ruijgrok, G.,Kok, K.,Armstrong, Z.W.B.,Aerts, J.M.F.G.,van der Marel, G.A.,Rovira, C.,Davies, G.J.,Artola, M.,Codee, J.D.C.,Overkleeft, H.S.
Conformational and Electronic Variations in 1,2- and 1,5a-Cyclophellitols and their Impact on Retaining alpha-Glucosidase Inhibition.
Chemistry, 30:e202400723-e202400723, 2024

PubMed Abstract: Glycoside hydrolases (glycosidases) take part in myriad biological processes and are important therapeutic targets. Competitive and mechanism-based inhibitors are useful tools to dissect their biological role and comprise a good starting point for drug discovery. The natural product, cyclophellitol, a mechanism-based, covalent and irreversible retaining β-glucosidase inhibitor has inspired the design of diverse α- and β-glycosidase inhibitor and activity-based probe scaffolds. Here, we sought to deepen our understanding of the structural and functional requirements of cyclophellitol-type compounds for effective human α-glucosidase inhibition. We synthesized a comprehensive set of α-configured 1,2- and 1,5a-cyclophellitol analogues bearing a variety of electrophilic traps. The inhibitory potency of these compounds was assessed towards both lysosomal and ER retaining α-glucosidases. These studies revealed the 1,5a-cyclophellitols to be the most potent retaining α-glucosidase inhibitors, with the nature of the electrophile determining inhibitory mode of action (covalent or non-covalent). DFT calculations support the ability of the 1,5a-cyclophellitols, but not the 1,2-congeners, to adopt conformations that mimic either the Michaelis complex or transition state of α-glucosidases.

PubMed: 38623783
DOI: 10.1002/chem.202400723

Experimental method

X-RAY DIFFRACTION (1.9 Å)