7T8G

G93A mutant of human SOD1 bound with MR6-8-2 in P21 space group

Summary for 7T8G

• Entry DOI: 10.2210/pdb7t8g/pdb
• Descriptor: Superoxide dismutase [Cu-Zn], ZINC ION, ~{N}-(pyridin-3-ylmethyl)-2-selanyl-benzamide, ... (7 entities in total)
• Functional Keywords: sod1, als, drug discovery, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 32857.35

Authors

Amporndanai, K.,Hasnain, S.S. (deposition date: 2021-12-16, release date: 2023-01-25, Last modification date: 2024-09-25)

Primary citation

Watanabe, S.,Amporndanai, K.,Awais, R.,Latham, C.,Awais, M.,O'Neill, P.M.,Yamanaka, K.,Hasnain, S.S.
Ebselen analogues delay disease onset and its course in fALS by on-target SOD-1 engagement.
Sci Rep, 14:12118-12118, 2024

PubMed Abstract: Amyotrophic lateral sclerosis (ALS) selectively affects motor neurons. SOD1 is the first causative gene to be identified for ALS and accounts for at least 20% of the familial (fALS) and up to 4% of sporadic (sALS) cases globally with some geographical variability. The destabilisation of the SOD1 dimer is a key driving force in fALS and sALS. Protein aggregation resulting from the destabilised SOD1 is arrested by the clinical drug ebselen and its analogues (MR6-8-2 and MR6-26-2) by redeeming the stability of the SOD1 dimer. The in vitro target engagement of these compounds is demonstrated using the bimolecular fluorescence complementation assay with protein-ligand binding directly visualised by co-crystallography in G93A SOD1. MR6-26-2 offers neuroprotection slowing disease onset of SOD1 mice by approximately 15 days. It also protected neuromuscular junction from muscle denervation in SOD1 mice clearly indicating functional improvement.

PubMed: 38802492
DOI: 10.1038/s41598-024-62903-5

Experimental method

X-RAY DIFFRACTION (1.35 Å)