7BSX

SDR protein NapW-NADP

Summary for 7BSX

• Entry DOI: 10.2210/pdb7bsx/pdb
• Descriptor: Short chain dehydrogenase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE (3 entities in total)
• Functional Keywords: sdr, rossmann, resistance, nadph, antibiotic, oxidoreductase
• Biological source: Streptomyces lusitanus
• Total number of polymer chains: 8
• Total formula weight: 295974.42

Authors

Wen, W.H.,Tang, G.L. (deposition date: 2020-03-31, release date: 2021-10-06, Last modification date: 2023-11-29)

Primary citation

Wen, W.H.,Zhang, Y.,Zhang, Y.Y.,Yu, Q.,Jiang, C.C.,Tang, M.C.,Pu, J.Y.,Wu, L.,Zhao, Y.L.,Shi, T.,Zhou, J.,Tang, G.L.
Reductive inactivation of the hemiaminal pharmacophore for resistance against tetrahydroisoquinoline antibiotics.
Nat Commun, 12:7085-7085, 2021

PubMed Abstract: Antibiotic resistance is becoming one of the major crises, among which hydrolysis reaction is widely employed by bacteria to destroy the reactive pharmacophore. Correspondingly, antibiotic producer has canonically co-evolved this approach with the biosynthetic capability for self-resistance. Here we discover a self-defense strategy featuring with reductive inactivation of hemiaminal pharmacophore by short-chain dehydrogenases/reductases (SDRs) NapW and homW, which are integrated with the naphthyridinomycin biosynthetic pathway. We determine the crystal structure of NapW·NADPH complex and propose a catalytic mechanism by molecular dynamics simulation analysis. Additionally, a similar detoxification strategy is identified in the biosynthesis of saframycin A, another member of tetrahydroisoquinoline (THIQ) antibiotics. Remarkably, similar SDRs are widely spread in bacteria and able to inactive other THIQ members including the clinical anticancer drug, ET-743. These findings not only fill in the missing intracellular events of temporal-spatial shielding mode for cryptic self-resistance during THIQs biosynthesis, but also exhibit a sophisticated damage-control in secondary metabolism and general immunity toward this family of antibiotics.

PubMed: 34873166
DOI: 10.1038/s41467-021-27404-3

Experimental method

X-RAY DIFFRACTION (2 Å)