6JZ2

b-glucuronidase from Ruminococcus gnavus in complex with uronic isofagomine at 1.3 Angstroms resolution

Summary for 6JZ2

• Entry DOI: 10.2210/pdb6jz2/pdb
• Descriptor: Beta-glucuronidase, (3S,4R,5R)-4,5-dihydroxypiperidine-3-carboxylic acid, (4R)-2-METHYLPENTANE-2,4-DIOL, ... (5 entities in total)
• Functional Keywords: b-glucuronidase, hydrolase
• Biological source: Ruminococcus gnavus
• Total number of polymer chains: 2
• Total formula weight: 146450.79

Authors

Dashnyam, P.,Lin, H.Y. (deposition date: 2019-04-30, release date: 2020-06-10, Last modification date: 2023-11-22)

Primary citation

Dashnyam, P.,Lin, H.Y.,Chen, C.Y.,Gao, S.,Yeh, L.F.,Hsieh, W.C.,Tu, Z.,Lin, C.H.
Substituent Position of Iminocyclitols Determines the Potency and Selectivity for Gut Microbial Xenobiotic-Reactivating Enzymes.
J.Med.Chem., 63:4617-4627, 2020

PubMed Abstract: Selective inhibitors of gut bacterial β-glucuronidases (GUSs) are of particular interest in the prevention of xenobiotic-induced toxicities. This study reports the first structure-activity relationships on potency and selectivity of several iminocyclitols (-) for the GUSs. Complex structures of GUS with - explained how charge, conformation, and substituent of iminocyclitols affect their potency and selectivity. N1 of uronic isofagomine () made strong electrostatic interactions with two catalytic glutamates of GUSs, resulting in the most potent inhibition ( ≥ 11 nM). C6-propyl analogue of () displayed 700-fold selectivity for opportunistic bacterial GUSs ( = 74 nM for GUS and 51.8 μM for GUS). In comparison with , there was 200-fold enhancement in the selectivity, which was attributed to differential interactions between the propyl group and loop 5 residues of the GUSs. The results provide useful insights to develop potent and selective inhibitors for undesired GUSs.

PubMed: 32105467
DOI: 10.1021/acs.jmedchem.9b01918

Experimental method

X-RAY DIFFRACTION (1.29 Å)