7SF4

M. tb EgtD in complex with imatinib

Summary for 7SF4

• Entry DOI: 10.2210/pdb7sf4/pdb
• Descriptor: Histidine N-alpha-methyltransferase, 2-AMINO-4-PYRIDYL-PYRIMIDINE, GLYCEROL, ... (5 entities in total)
• Functional Keywords: ergothioneine biosynthesis pathway, rossmann fold domain, histidine binding site, sam dependent methyltransferase, transferase
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 2
• Total formula weight: 72023.06

Authors

Sudasinghe, T.D.,Ronning, D.R. (deposition date: 2021-10-03, release date: 2021-12-01, Last modification date: 2023-10-18)

Primary citation

Sudasinghe, T.D.,Banco, M.T.,Ronning, D.R.
Inhibitors of Mycobacterium tuberculosis EgtD target both substrate binding sites to limit hercynine production.
Sci Rep, 11:22240-22240, 2021

PubMed Abstract: Ergothioneine (EGT) is a low molecular weight histidine betaine essential in all domains of life but only synthesized by selected few organisms. Synthesis of EGT by Mycobacterium tuberculosis (M. tb) is critical for maintaining bioenergetic homeostasis and protecting the bacterium from alkylating agents, oxidative stress, and anti-tubercular drugs. EgtD, an S-adenosylmethionine-dependent methyltransferase (AdoMet), catalyzes the trimethylation of L-Histidine to initiate EGT biosynthesis and this reaction has been shown to be essential for EGT production in mycobacteria and for long-term infection of murine macrophages by M. tb. In this work, library screening and structure-guided strategies identified multiple classes of M. tb EgtD inhibitors that bind in various regions of the enzyme active site. X-ray crystal structures of EgtD-inhibitor complexes confirm that L-Histidine analogs bind solely to the L-Histidine binding site while drug-like inhibitors, such as TGX-221, and S-Glycyl-H-1152 span both the L-Histidine and AdoMet binding sites. These enzyme-inhibitor complexes provide detailed structural information of compound scaffolds useful for developing more potent inhibitors that could shorten Tuberculosis treatment regimens by weakening important bacterial defenses.

PubMed: 34782676
DOI: 10.1038/s41598-021-01526-6

Experimental method

X-RAY DIFFRACTION (2.39 Å)