6y91

Crystal structure of malate dehydrogenase from Plasmodium Falciparum in complex with NADH

spinqualitylabelsall models 6y91, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6y91 is a 4 chain structure with sequence from Plasmodium falciparum. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.5Å Ligands: NAD Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q6VVP7_PLAFA Publication Abstract from PubMed Malate dehydrogenases (MDHs) sustain tumor growth and carbon metabolism by pathogens including Plasmodium falciparum. However, clinical success of MDH inhibitors is absent, as current small molecule approaches targeting the active site are unselective. The presence of an allosteric binding site at oligomeric interface allows the development of more specific inhibitors. To this end we performed a differential NMR-based screening of 1500 fragments to identify fragments that bind at the oligomeric interface. Subsequent biophysical and biochemical experiments of an identified fragment indicate an allosteric mechanism of 4-(3,4-difluorophenyl) thiazol-2-amine (4DT) inhibition by impacting the formation of the active site loop, located >30 A from the 4DT binding site. Further characterization of the more tractable homolog 4-phenylthiazol-2-amine (4PA) and 16 other derivatives are also reported. These data pave the way for downstream development of more selective molecules by utilizing the oligomeric interfaces showing higher species sequence divergence than the MDH active site. A fragment-based approach identifies an allosteric pocket that impacts malate dehydrogenase activity.,Reyes Romero A, Lunev S, Popowicz GM, Calderone V, Gentili M, Sattler M, Plewka J, Taube M, Kozak M, Holak TA, Domling ASS, Groves MR Commun Biol. 2021 Aug 10;4(1):949. doi: 10.1038/s42003-021-02442-1. PMID:34376783 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Malate Dehydrogenase 3D structures

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