3wmc
Crystal structure of insect beta-N-acetyl-D-hexosaminidase OfHex1 complexed with naphthalimide derivative Q2
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 PubMedSelective inhibition of function-specific beta-GlcNAcase has great potential in terms of drug design and biological research. The symmetrical bis-naphthalimide M-31850 was previously obtained by screening for specificity against human glycoconjugate-lytic beta-GlcNAcase. Using protein-ligand co-crystallization and molecular docking, we designed an unsymmetrical dyad of naphthalimide and thiadiazole, Q2, that changes naphthalimide specificity from against a human glycoconjugate-lytic beta-GlcNAcase to against insect and bacterial chitinolytic beta-GlcNAcases. The crystallographic and in silico studies reveal that the naphthalimide ring can be utilized to bind different parts of these enzyme homologs, providing a new starting point to design specific inhibitors. Moreover, Q2-induced closure of the substrate binding pocket is the structural basis for its 13-fold increment in inhibitory potency. Q2 is the first non-carbohydrate inhibitor against chitinolytic beta-GlcNAcases. This study provides a useful example of structure-based rationally designed inhibitors as potential pharmaceuticals or pesticides. A crystal structure-guided rational design switching non-carbohydrate inhibitors' specificity between two beta-GlcNAcase homologs.,Liu T, Guo P, Zhou Y, Wang J, Chen L, Yang H, Qian X, Yang Q Sci Rep. 2014 Aug 26;4:6188. doi: 10.1038/srep06188. PMID:25155420[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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