7x12
Crystal structure of ME1 in complex with NADPHCrystal structure of ME1 in complex with NADPH
Structural highlights
FunctionPublication Abstract from PubMedNADP(+)-dependent malic enzyme 1 (ME1) decarboxylates malate to form pyruvate and NADPH in the cytoplasm, where it mediates diverse biological functions related to the generation of lipids and other cellular building blocks. As such, ME1 has been implicated in the progression of cancers and has received attention as a promising drug target. Here we report the identification of a novel small-molecule inhibitor of ME1, designated AS1134900. AS1134900 is highly selective for ME1 compared with ME2 and uncompetitively inhibits ME1 activity in the presence of its substrates NADP(+) and malate. In addition, X-ray crystal structure analysis of the enzyme-inhibitor complex revealed that AS1134900 binds outside the ME1 active site in a novel allosteric site. Structural comparison of the ME1 quaternary complex with AS1134900, NADPH, and Mn(2+), alongside known crystal structures of malic enzymes, indicated the determined crystal ME1-inhibitor complex is in the open form conformation. These results provide insights and a starting point for further discovery of drugs that inhibit ME1 activity in cancer cells. Discovery and Characterization of a Novel Allosteric Small-Molecule Inhibitor of NADP(+)-Dependent Malic Enzyme 1.,Yoshida T, Kawabe T, Cantley LC, Lyssiotis CA Biochemistry. 2022 Aug 2;61(15):1548-1553. doi: 10.1021/acs.biochem.2c00123. Epub, 2022 Jul 12. PMID:35819845[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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