8RVK

Maltodextrin phosphorylase (MalP) in complex with a alpha-1,2-cyclophellitol analogue

これはPDB形式変換不可エントリーです。

8RVK の概要

• エントリーDOI: 10.2210/pdb8rvk/pdb
• 分子名称: Maltodextrin phosphorylase, (3~{a}~{R},4~{R},5~{R},6~{R},7~{a}~{S})-6-(hydroxymethyl)-4,5-bis(oxidanyl)-3~{a},4,5,6,7,7~{a}-hexahydro-3~{H}-1,3-benzoxazol-2-one, 1,2-ETHANEDIOL, ... (6 entities in total)
• 機能のキーワード: phosphorylase, glycosyltransferase, gt35, carbohydrate metabolism, transferase
• 由来する生物種: Escherichia coli K-12
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 186434.01

構造登録者

Bennett, M.,Ofman, T.P.,Overkleeft, H.S.,Davies, G.J. (登録日: 2024-02-01, 公開日: 2024-05-15, 最終更新日: 2024-06-12)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.18 Å)