6A9O
Rational discovery of a SOD1 tryptophan oxidation inhibitor with therapeutic potential for amyotrophic lateral sclerosis
Summary for 6A9O
| Entry DOI | 10.2210/pdb6a9o/pdb |
| Descriptor | Superoxide dismutase [Cu-Zn], ZINC ION, DIMETHYL SULFOXIDE, ... (7 entities in total) |
| Functional Keywords | dismutase, dimer, oxidation, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 10 |
| Total formula weight | 161526.16 |
| Authors | Manjula, R.,Padmanabhan, B. (deposition date: 2018-07-14, release date: 2019-07-17, Last modification date: 2024-11-20) |
| Primary citation | Manjula, R.,Unni, S.,Wright, G.S.A.,Bharath M M, S.,Padmanabhan, B. Rational discovery of a SOD1 tryptophan oxidation inhibitor with therapeutic potential for amyotrophic lateral sclerosis. J.Biomol.Struct.Dyn., 37:3936-3946, 2019 Cited by PubMed Abstract: Formation of Cu, Zn superoxide dismutase 1 (SOD1) protein inclusions within motor neurons is one of the principal characteristics of SOD1-related amyotrophic lateral sclerosis (ALS). A hypothesis as to the nature of SOD1 aggregation implicates oxidative damage to a solvent-exposed tryptophan as causative. Here, we chart the discovery of a phenanthridinone based compound (Lig9) from the NCI Diversity Set III by rational methods by screening and crystallographic validation. The crystal structure of the complex with SOD1, refined to 2.5 Å, revealed that Lig9 binds the SOD1 β-barrel in the β-strand 2 and 3 region which is known to scaffold SOD1 fibrillation. The phenanthridinone moiety makes a substantial π-π interaction with Trp32 of SOD1. The compound possesses a significant binding affinity for SOD1 and inhibits oxidation of Trp32; a critical residue for SOD1 aggregation. Thus, Lig9 is a good candidate from which to develop a new library of SOD1 aggregation inhibitors through protection of Trp32 oxidation. Communicated by Ramaswamy H. Sarma. PubMed: 30286701DOI: 10.1080/07391102.2018.1531787 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.5 Å) |
Structure validation
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