7WJV

Crystal structure of human liver FBPase complexed with an covalent inhibitor

Summary for 7WJV

• Entry DOI: 10.2210/pdb7wjv/pdb
• Descriptor: Fructose-1,6-bisphosphatase 1, ADENOSINE MONOPHOSPHATE, 1,2-BENZISOTHIAZOL-3(2H)-ONE 1,1-DIOXIDE, ... (7 entities in total)
• Functional Keywords: classification: hydrolase organism(s): homo sapiens expression system: escherichia coli bl21(de3) inhibitor: covalent binding c128, cytosolic protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 154875.51

Authors

Cao, H.,Huang, Y.,Ren, Y.,Wan, J. (deposition date: 2022-01-08, release date: 2022-07-13, Last modification date: 2024-10-23)

Primary citation

Wen, W.,Cao, H.,Xu, Y.,Ren, Y.,Rao, L.,Shao, X.,Chen, H.,Wu, L.,Liu, J.,Su, C.,Peng, C.,Huang, Y.,Wan, J.
N -Acylamino Saccharin as an Emerging Cysteine-Directed Covalent Warhead and Its Application in the Identification of Novel FBPase Inhibitors toward Glucose Reduction.
J.Med.Chem., 65:9126-9143, 2022

PubMed Abstract: With a resurgence of covalent drugs, there is an urgent need for the identification of new moieties capable of cysteine bond formation. Herein, we report on the -acylamino saccharin moieties capable of novel covalent reactions with cysteine. Their utility as alternative electrophilic warheads was demonstrated through the covalent modification of fructose-1,6-bisphosphatase (FBPase), a promising target associated with cancer and type 2 diabetes. The cocrystal structure of title compound bound with FBPase unexpectedly revealed that the -acylamino saccharin moiety worked as an electrophile warhead that covalently modified the noncatalytic C128 site in FBPase while releasing saccharin, suggesting a previously undiscovered covalent reaction mechanism of saccharin derivatives with cysteine. Treatment of title compound displayed potent inhibition of glucose production in vitro and in vivo. This newly discovered reactive warhead supplements the current repertoire of cysteine covalent modifiers while avoiding some of the limitations generally associated with established moieties.

PubMed: 35786925
DOI: 10.1021/acs.jmedchem.2c00336

Experimental method

X-RAY DIFFRACTION (1.724 Å)