8SPM

Crystal structure of NikA in complex Ni-AMA

8SPM の概要

• エントリーDOI: 10.2210/pdb8spm/pdb
• 分子名称: Nickel ABC transporter, nickel/metallophore periplasmic binding protein, Aspergillomarasmine A, NICKEL (II) ION, ... (4 entities in total)
• 機能のキーワード: inhibitor, complex, virulence, transport protein
• 由来する生物種: Escherichia coli
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 56429.31

構造登録者

Sychantha, D.,Prehna, G.,Wright, G.D. (登録日: 2023-05-03, 公開日: 2024-04-10, 最終更新日: 2024-06-05)

主引用文献

Sychantha, D.,Chen, X.,Koteva, K.,Prehna, G.,Wright, G.D.
Targeting bacterial nickel transport with aspergillomarasmine A suppresses virulence-associated Ni-dependent enzymes.
Nat Commun, 15:4036-4036, 2024

PubMed Abstract: Microbial Ni homeostasis underpins the virulence of several clinical pathogens. Ni is an essential cofactor in urease and [NiFe]-hydrogenases involved in colonization and persistence. Many microbes produce metallophores to sequester metals necessary for their metabolism and starve competing neighboring organisms. The fungal metallophore aspergillomarasmine A (AMA) shows narrow specificity for Zn, Ni, and Co. Here, we show that this specificity allows AMA to block the uptake of Ni and attenuate bacterial Ni-dependent enzymes, offering a potential strategy for reducing virulence. Bacterial exposure to AMA perturbs H metabolism, ureolysis, struvite crystallization, and biofilm formation and shows efficacy in a Galleria mellonella animal infection model. The inhibition of Ni-dependent enzymes was aided by Zn which complexes with AMA and competes with the native nickelophore for the uptake of Ni. Biochemical analyses demonstrated high-affinity binding of AMA-metal complexes to NikA, the periplasmic substrate-binding protein of the Ni uptake system. Structural examination of NikA in complex with Ni-AMA revealed that the coordination geometry of Ni-AMA mimics the native ligand, Ni-(L-His), providing a structural basis for binding AMA-metal complexes. Structure-activity relationship studies of AMA identified regions of the molecule that improve NikA affinity and offer potential routes for further developing this compound as an anti-virulence agent.

PubMed: 38740750
DOI: 10.1038/s41467-024-48232-1

実験手法

X-RAY DIFFRACTION (2.15 Å)