8D6K

Sco GlgEI-V279S in complex with cyclohexyl carbasugar

Summary for 8D6K

• Entry DOI: 10.2210/pdb8d6k/pdb
• Descriptor: Alpha-1,4-glucan:maltose-1-phosphate maltosyltransferase 1, DI(HYDROXYETHYL)ETHER, (1R,4S,5S,6R)-4-(cyclohexylamino)-5,6-dihydroxy-2-(hydroxymethyl)cyclohex-2-en-1-yl alpha-D-glucopyranoside, ... (4 entities in total)
• Functional Keywords: complex with glge, transferase
• Biological source: Streptomyces coelicolor A3(2)
• Total number of polymer chains: 2
• Total formula weight: 153734.15

Authors

Jayasinghe, T.J.,Ronning, D.R. (deposition date: 2022-06-06, release date: 2022-10-19, Last modification date: 2023-10-18)

Primary citation

Thanvi, R.,Jayasinghe, T.D.,Kapil, S.,Obadawo, B.S.,Ronning, D.R.,Sucheck, S.J.
Synthesis of C 7 /C 8 -cyclitols and C 7 N-aminocyclitols from maltose and X-ray crystal structure of Streptomyces coelicolor GlgEI V279S in a complex with an amylostatin GXG-like derivative.
Front Chem, 10:950433-950433, 2022

PubMed Abstract: C/C-cyclitols and CN-aminocyclitols find applications in the pharmaceutical sector as α-glucosidase inhibitors and in the agricultural sector as fungicides and insecticides. In this study, we identified C/C-cyclitols and CN-aminocyclitols as potential inhibitors of () GlgEI-V279S based on the docking scores. The protein and the ligand (targets , , and ) were prepared, the states were generated at pH 7.0 ± 2.0, and the ligands were docked into the active sites of the receptor Glide™. The synthetic route to these targets was similar to our previously reported route used to obtain 4-⍺-glucoside of valienamine (), except the protecting group for target was a -bromobenzyl (PBB) ether to preserve the alkene upon deprotection. While compounds - did not inhibit GlgEI-V279S at the concentrations evaluated, an X-ray crystal structure of the GlgE1-V279S/ complex was solved to a resolution of 2.73 Å. This structure allowed assessment differences and commonality with our previously reported inhibitors and was useful for identifying enzyme-compound interactions that may be important for future inhibitor development. The Asp 394 nucleophile formed a bidentate hydrogen bond interaction with the exocyclic oxygen atoms (C(3)-OH and C(7)-OH) similar to the observed interactions with the GlgEI-V279S in a complex with (PDB:7MGY). In addition, the data suggest replacing the cyclohexyl group with more isosteric and hydrogen bond-donating groups to increase binding interactions in the + 1 binding site.

PubMed: 36157042
DOI: 10.3389/fchem.2022.950433

Experimental method

X-RAY DIFFRACTION (2.73 Å)