7wjv

Crystal structure of human liver FBPase complexed with an covalent inhibitor

spinqualitylabelsall models 7wjv, resolution 1.72Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7wjv is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: AMP, GOL, LSA, MG, PMQ Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [Q2TU34_HUMAN] Publication Abstract from PubMed 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 N-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 W8 bound with FBPase unexpectedly revealed that the N-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 W8 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. N-Acylamino Saccharin as an Emerging Cysteine-Directed Covalent Warhead and Its Application in the Identification of Novel FBPase Inhibitors toward Glucose Reduction.,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 J Med Chem. 2022 Jul 4. doi: 10.1021/acs.jmedchem.2c00336. PMID:35786925 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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