8SPM
Crystal structure of NikA in complex Ni-AMA
Summary for 8SPM
| Entry DOI | 10.2210/pdb8spm/pdb |
| Descriptor | Nickel ABC transporter, nickel/metallophore periplasmic binding protein, Aspergillomarasmine A, NICKEL (II) ION, ... (4 entities in total) |
| Functional Keywords | inhibitor, complex, virulence, transport protein |
| Biological source | Escherichia coli |
| Total number of polymer chains | 1 |
| Total formula weight | 56429.31 |
| Authors | Sychantha, D.,Prehna, G.,Wright, G.D. (deposition date: 2023-05-03, release date: 2024-04-10, Last modification date: 2024-06-05) |
| Primary citation | 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 Cited by 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: 38740750DOI: 10.1038/s41467-024-48232-1 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.15 Å) |
Structure validation
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