6BUV

Structure of Mycobacterium tuberculosis NadD in complex with inhibitor [(1~{R},2~{R},5~{S})-5-methyl-2-propan-2-yl-cyclohexyl] 2-[3-methyl-2-(phenoxymethyl)benzimidazol-1-yl]ethanoate

Summary for 6BUV

• Entry DOI: 10.2210/pdb6buv/pdb
• Descriptor: nicotinate mononucleotide adenylyltransferase NadD, SODIUM ION, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: rossman fold, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Mycobacterium tuberculosis; More
• Total number of polymer chains: 2
• Total formula weight: 45340.39

Authors

Rodionova, I.A.,Reed, R.W.,Sorci, L.,Osterman, A.L.,Korotkov, K.V. (deposition date: 2017-12-11, release date: 2018-12-12, Last modification date: 2024-05-01)

Primary citation

Osterman, A.L.,Rodionova, I.,Li, X.,Sergienko, E.,Ma, C.T.,Catanzaro, A.,Pettigrove, M.E.,Reed, R.W.,Gupta, R.,Rohde, K.H.,Korotkov, K.V.,Sorci, L.
Novel Antimycobacterial Compounds Suppress NAD Biogenesis by Targeting a Unique Pocket of NaMN Adenylyltransferase.
Acs Chem.Biol., 14:949-958, 2019

PubMed Abstract: Conventional treatments to combat the tuberculosis (TB) epidemic are falling short, thus encouraging the search for novel antitubercular drugs acting on unexplored molecular targets. Several whole-cell phenotypic screenings have delivered bioactive compounds with potent antitubercular activity. However, their cellular target and mechanism of action remain largely unknown. Further evaluation of these compounds may include their screening in search for known antitubercular drug targets hits. Here, a collection of nearly 1400 mycobactericidal compounds was screened against Mycobacterium tuberculosis NaMN adenylyltransferase ( MtNadD), a key enzyme in the biogenesis of NAD cofactor that was recently validated as a new drug target for dormant and active tuberculosis. We found three chemotypes that efficiently inhibit MtNadD in the low micromolar range in vitro. SAR and cheminformatics studies of commercially available analogues point to a series of benzimidazolium derivatives, here named N2, with bactericidal activity on different mycobacteria, including M. abscessus, multidrug-resistant M. tuberculosis, and dormant M. smegmatis. The on-target activity was supported by the increased resistance of an M. smegmatis strain overexpressing the target and by a rapid decline in NAD(H) levels. A cocrystal structure of MtNadD with N2-8 inhibitor reveals that the binding of the inhibitor induced the formation of a new quaternary structure, a dimer-of-dimers where two copies of the inhibitor occupy symmetrical positions in the dimer interface, thus paving the way for the development of a new generation of selective MtNadD bioactive inhibitors. All these results strongly suggest that pharmacological inhibition of MtNadD is an effective strategy to combat dormant and resistant Mtb strains.

PubMed: 30969758
DOI: 10.1021/acschembio.9b00124

Experimental method

X-RAY DIFFRACTION (1.86 Å)