8rw3 | pdb_00008rw3

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

spinqualitylabelsall models 8rw3, resolution 1.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8rw3 is a 3 chain structure with sequence from Cellvibrio japonicus Ueda107. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.9Å Ligands: EDO, GDQ, OXL, PG4, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function OL4AG_CELJU Alpha-transglucosylase that specifically transfers single glucosyl units from alpha(1->4)-glucans to the non-reducing terminal 4-OH of glucose and alpha(1->4)- and alpha(1->6)-linked glucosyl residues. Acts on amylose, amylopectin, glycogen and maltooligosaccharides, with the highest activity with maltotriose as a donor, and also accepts maltose. Does not act as a hydrolase: weak hydrolysis activity is only observed on the disaccharide maltose. Publication Abstract from PubMed 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 beta-glucosidase inhibitor has inspired the design of diverse alpha- and beta-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 alpha-glucosidase inhibition. We synthesized a comprehensive set of alpha-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 alpha-glucosidases. These studies revealed the 1,5a-cyclophellitols to be the most potent retaining alpha-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 alpha-glucosidases. Conformational and Electronic Variations in 1,2- and 1,5a-Cyclophellitols and their Impact on Retaining alpha-Glucosidase Inhibition.,Ofman TP, Heming JJA, Nin-Hill A, Kullmer F, Moran E, Bennett M, Steneker R, Klein AM, Ruijgrok G, Kok K, Armstrong ZWB, Aerts JMFG, van der Marel GA, Rovira C, Davies GJ, Artola M, Codee JDC, Overkleeft HS Chemistry. 2024 Apr 16:e202400723. doi: 10.1002/chem.202400723. PMID:38623783 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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