3WMC

Crystal structure of insect beta-N-acetyl-D-hexosaminidase OfHex1 complexed with naphthalimide derivative Q2

Summary for 3WMC

• Entry DOI: 10.2210/pdb3wmc/pdb
• Related: 3NSM 3NSN 3OZO 3OZP 3S6T 3VTR 3WMB
• Descriptor: Beta-hexosaminidase, 6-(dimethylamino)-2-(2-{[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]amino}ethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: chitinase, glycosyl hydrolase, insect, ostrinia furnacalis, hydrolase
• Biological source: Ostrinia furnacalis (Asian corn borer)
• Total number of polymer chains: 1
• Total formula weight: 66389.80

Authors

Chen, L.,Zhou, Y.,Chen, L.,Yang, Q. (deposition date: 2013-11-16, release date: 2014-11-05, Last modification date: 2024-10-30)

Primary citation

Liu, T.,Guo, P.,Zhou, Y.,Wang, J.,Chen, L.,Yang, H.,Qian, X.,Yang, Q.
A crystal structure-guided rational design switching non-carbohydrate inhibitors' specificity between two beta-GlcNAcase homologs
Sci Rep, 4:6188-6188, 2014

PubMed Abstract: Selective inhibition of function-specific β-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 β-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 β-GlcNAcase to against insect and bacterial chitinolytic β-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 β-GlcNAcases. This study provides a useful example of structure-based rationally designed inhibitors as potential pharmaceuticals or pesticides.

PubMed: 25155420
DOI: 10.1038/srep06188

Experimental method

X-RAY DIFFRACTION (2.095 Å)