6LS5

Structure of human liver FBPase complexed with covalent allosteric inhibitor

Summary for 6LS5

• Entry DOI: 10.2210/pdb6ls5/pdb
• Descriptor: Fructose-1,6-bisphosphatase 1, 2-(ethyldisulfanyl)-1,3-benzothiazole, ADENOSINE MONOPHOSPHATE, ... (5 entities in total)
• Functional Keywords: fbpase, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 156819.51

Authors

Yunyuan, H.,Rongrong, S.,Yixiang, X.,Shuaishuai, N.,Yanliang, R.,Jian, L.,Jian, W. (deposition date: 2020-01-17, release date: 2020-05-27, Last modification date: 2024-11-06)

Primary citation

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.
Identification of the New Covalent Allosteric Binding Site of Fructose-1,6-bisphosphatase with Disulfiram Derivatives toward Glucose Reduction.
J.Med.Chem., 63:6238-6247, 2020

PubMed Abstract: 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 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 might moderately reduce blood glucose output . 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.

PubMed: 32375478
DOI: 10.1021/acs.jmedchem.0c00699

Experimental method

X-RAY DIFFRACTION (2.031 Å)