5y1b | pdb_00005y1b
Crystal Structure of insect beta-N-acetyl-D-hexosaminidase OfHex1 complexed with a berberine derivative (SYSU-00679)
Structural highlights
FunctionHEXC_OSTFU Hydrolyzes one beta-GlcNAc unit at a time from the non-reducing ends of substrates, with a preference for shorter substrates. The 2-acetamido group and the beta-glycoside bond linkage in the substrate are required for its activity. Active with p-nitrophenyl (pNP)-beta-GlcNAc, pNP-beta-GalNAc and chitooligosaccharides (degree of polymerization from 2 to 6), but not with the complex N-glycan substrate (GlcNAcbeta-1,2Manalpha-1,6)(GlcNAcbeta-1,2Manalpha-1,3)Manbeta-1,4GlcNAcbeta-1,4GlcNAc-PA (GnGn-PA), pNP-alpha-GlcNAc or with the long polymer colloidal chitin. Involved in chitin catabolism (PubMed:18959754). Involved in the degradation of old cuticle during the pupation stage (PubMed:21106526).[1] [2] Publication Abstract from PubMedBerberine is a traditional medicine that has multiple medicinal and agricultural applications. However, little is known about whether berberine can be a bioactive molecule toward carbohydrate-active enzymes, which play numerous vital roles in the life process. In this study, berberine and its analogs were discovered to be competitive inhibitors of glycoside hydrolase family 20 beta-N-acetyl-d-hexosaminidase (GH20 Hex) and GH18 chitinase from both humans and the insect pest Ostrinia furnacalis Berberine and its analog SYSU-1 inhibit insect GH20 Hex from O. furnacalis (OfHex1), with Ki values of 12 and 8.5 mum, respectively. Co-crystallization of berberine and its analog SYSU-1 in complex with OfHex1 revealed that the positively charged conjugate plane of berberine forms pi-pi stacking interactions with Trp(490), which are vital to its inhibitory activity. Moreover, the 1,3-dioxole group of berberine binds an unexplored pocket formed by Trp(322), Trp(483), and Val(484), which also contributes to its inhibitory activity. Berberine was also found to be an inhibitor of human GH20 Hex (HsHexB), human GH18 chitinase (HsCht and acidic mammalian chitinase), and insect GH18 chitinase (OfChtI). Besides GH18 and GH20 enzymes, berberine was shown to weakly inhibit human GH84 O-GlcNAcase (HsOGA) and Saccharomyces cerevisiae GH63 alpha-glucosidase I (ScGluI). By analyzing the published crystal structures, berberine was revealed to bind with its targets in an identical mechanism, namely via pi-pi stacking and electrostatic interactions with the aromatic and acidic residues in the binding pockets. This paper reports new molecular targets of berberine and may provide a berberine-based scaffold for developing multitarget drugs. Glycoside hydrolase family 18 and 20 enzymes are novel targets of the traditional medicine berberine.,Duan Y, Liu T, Zhou Y, Dou T, Yang Q J Biol Chem. 2018 Oct 5;293(40):15429-15438. doi: 10.1074/jbc.RA118.004351. Epub , 2018 Aug 22. PMID:30135205[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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