7XX3
Crystal structure of human Superoxide Dismutase (SOD1) in complex with a fungal metabolite molecule, Phialomustin B (PB)
Summary for 7XX3
| Entry DOI | 10.2210/pdb7xx3/pdb |
| Descriptor | Superoxide dismutase [Cu-Zn], ZINC ION, GLYCEROL, ... (6 entities in total) |
| Functional Keywords | superoxide dismutase, protein aggregation, modulator, toxic trimer, oxidoreductase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 10 |
| Total formula weight | 192834.62 |
| Authors | Padmanabhan, B.,Unni, S. (deposition date: 2022-05-28, release date: 2023-12-13, Last modification date: 2025-02-26) |
| Primary citation | Unni, S.,Kommu, P.,Aouti, S.,Nalli, Y.,Bharath, M.M.S.,Ali, A.,Padmanabhan, B. Structural insights into the modulation Of SOD1 aggregation By a fungal metabolite Phialomustin-B: Therapeutic potential in ALS. Plos One, 19:e0298196-e0298196, 2024 Cited by PubMed Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal human motor neuron disease leading to muscle atrophy and paralysis. Mutations in superoxide dismutase 1 (SOD1) are associated with familial ALS (fALS). The SOD1 mutants in ALS have a toxic-gain of function by destabilizing the functional SOD1 homodimer, consequently inducing fibril-like aggregation with a cytotoxic non-native trimer intermediate. Therefore, reducing SOD1 oligomerization via chemical modulators is an optimal therapy in ALS. Here, we report the discovery of Phialomustin-B, an unsaturated secondary metabolite from the endophytic fungus Phialophora mustea, as a modulator of SOD1 aggregation. The crystal structure of the SOD1-Phialomustin complex refined to 1.90 Å resolution demonstrated for the first time that the ligand binds to the dimer interface and the lateral region near the electrostatic loop. The aggregation analyses of SOD1WT and the disease mutant SOD1A4V revealed that Phialomustin-B reduces cytotoxic trimerization. We propose that Phialomustin-B is a potent lead molecule with therapeutic potential in fALS. PubMed: 38446760DOI: 10.1371/journal.pone.0298196 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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