8f57

Crystal structure of acetyltransferase Eis from M. tuberculosis in complex with inhibitor SGT1615

spinqualitylabelsall models 8f57, resolution 2.42Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8f57 is a 1 chain structure with sequence from Mycobacterium tuberculosis H37Rv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.42Å Ligands: DMS, GOL, PEG, XEL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function EIS_MYCTU May participate in pathogenesis, possibly by enhancing survival of the bacteria in host macrophages during infection. Publication Abstract from PubMed Over one and a half million people die of tuberculosis (TB) each year. Multidrug-resistant TB infections are especially dangerous, and new drugs are needed to combat them. The high cost and complexity of drug development make repositioning of drugs that are already in clinical use for other indications a potentially time- and money-saving avenue. In this study, we identified among existing drugs five compounds: azelastine, venlafaxine, chloroquine, mefloquine, and proguanil as inhibitors of acetyltransferase Eis from Mycobacterium tuberculosis, a causative agent of TB. Eis upregulation is a cause of clinically relevant resistance of TB to kanamycin, which is inactivated by Eis-catalyzed acetylation. Crystal structures of these drugs as well as chlorhexidine in complexes with Eis showed that these inhibitors were bound in the aminoglycoside binding cavity, consistent with their established modes of inhibition with respect to kanamycin. Among three additionally synthesized compounds, a proguanil analogue, designed based on the crystal structure of the Eis-proguanil complex, was 3-fold more potent than proguanil. The crystal structures of these compounds in complexes with Eis explained their inhibitory potencies. These initial efforts in rational drug repositioning can serve as a starting point in further development of Eis inhibitors. Discovery and Mechanistic Analysis of Structurally Diverse Inhibitors of Acetyltransferase Eis among FDA-Approved Drugs.,Pang AH, Green KD, Punetha A, Thamban Chandrika N, Howard KC, Garneau-Tsodikova S, Tsodikov OV Biochemistry. 2023 Jan 19. doi: 10.1021/acs.biochem.2c00658. PMID:36657084 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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