8zb5 | pdb_00008zb5
Crystal structure of NudC from Mycobacterium abscessus in complex with AMP
Structural highlights
FunctionPublication Abstract from PubMedNon-tuberculous mycobacteria (NTM) have emerged as an increasing threat to public health, due to the extreme antibiotic resistance. NADH pyrophosphatase (NudC) was proposed involving in mycobacterial resistance to the first line anti-tubercular drug isoniazid (INH) or its analog ethionamide (ETH), by hydrolyzing their NAD modified active forms (NAD-INH and NAD-ETH). In this study, we performed enzymatic and structural studies on NudC from M. abscessus (NudC(Mab)), which is highly resistant to isoniazid and emerging as the most worrisome NTM. We determined the crystal structures of NudC(Mab) in apo form, substrate NAD-bound form and product AMP-bound form. We observed the mode for the Nudix motif of NudC(Mab) capturing the pyrophosphate group of NAD mediated by three divalent cation ions, which provides details for understanding the mechanism on NudC hydrolyzing NAD(H) or NAD-capped substrate. Interestingly, our structures revealed a novel subclass NudC from mycobacteria characterized by a unique arginine residue on the conserved QPWPFPxS motif, as well as a unique tower domain that replaces a well-defined zinc-binding motif in E.coli NudC and catalytic domain of mammalian Nudt12. Thus, our structural studies on NudC(Mab) not only present a class of zinc independent NADH pyrophosphatase in mycobacteria, but also may facilitate the design of NudC inhibitors for the treatment of mycobacteria infections in combination with INH or ETH. Structural Studies on Mycobacterial NudC Reveal a Class of Zinc Independent NADH Pyrophosphatase.,Meng L, Sun Z, Zhang Y, Dong Y, Du X, Wu Y, Yuan Y, Sun Y, Xu Y, Ding H, Liu J, Xu J J Mol Biol. 2024 Dec 1;436(23):168864. doi: 10.1016/j.jmb.2024.168864. Epub 2024 , Nov 8. PMID:39521043[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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