6ls5

Structure of human liver FBPase complexed with covalent allosteric inhibitor

spinqualitylabelsall models 6ls5, resolution 2.03Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.031Å Ligands: AMP, EUF, MG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Fructose 1,6-bisphosphatase (FBPase) has attracted substantial interest as a target associated with cancer and type 2 diabetes. Herein, we found that disulfiram and its derivatives can potently inhibit FBPase by covalently binding to a new C128 allosteric site distinct from the original C128 site in APO FBPase. Further identification of the allosteric inhibition mechanism reveals that the covalent binding of a fragment of 214 will result in the movement of C128 and the dissociation of helix H4 (123-128), which in turn allows S123 to more easily form new hydrogen bonds with K71 and D74 in helix H3 (69-72), thereby inhibiting FBPase activity. Notably, both disulfiram and 212 might moderately reduce blood glucose output in vivo. Therefore, our current findings not only identify a new covalent allosteric site of FBPase but also establish a structural foundation and provide a promising way for the design of covalent allosteric drugs for glucose reduction. Identification of the New Covalent Allosteric Binding Site of Fructose-1,6-bisphosphatase with Disulfiram Derivatives toward Glucose Reduction.,Huang Y, Xu Y, Song R, Ni S, Liu J, Xu Y, Ren Y, Rao L, Wang Y, Wei L, Feng L, Su C, Peng C, Li J, Wan J J Med Chem. 2020 May 19. doi: 10.1021/acs.jmedchem.0c00699. PMID:32375478 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Fructose-1%2C6-bisphosphatase 3D structures

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