Crystal structure of an extracellular superoxide dismutase from Onchocerca volvulus and implications for parasite‐specific drug development. Issue 6 (1st June 2022)

• Record Type: Journal Article
• Authors: Moustafa, Amr; Perbandt, Markus; Liebau, Eva; Betzel, Christian; Falke, Sven
• Is Part Of: Acta crystallographica. Volume 78:Issue 6(2022)
• Page Start: 232
• Page End: 240
• Publication Date: 2022-06-01
• Subjects: X‐ray crystallography -- Cu/Zn superoxide dismutases -- metal ion coordination -- Onchocerca volvulus -- parasites -- docking -- drug targets; Crystallography -- Periodicals; Crystals -- Periodicals; 548
• DOI: 10.1107/S2053230X22005350
• Languages: English
• ISSNs: 2053-230X

Abstract

Abstract : An extracellular Cu/Zn superoxide dismutase from Onchocerca volvulus, the causative agent of human onchocerciasis, was purified and crystallized and the structure was solved at 1.55 Å resolution. The solution structure of the dimeric protein was verified using small‐angle X‐ray scattering. Initial docking studies utilizing previously identified superoxide dismutase inhibitors indicate the potential for future drug development targeting structural features outside the active site. Abstract : Superoxide dismutases (SODs) are metalloproteins that are responsible for the dismutation of superoxide anion radicals. SODs are consequently protective against oxidative damage to cellular components. Among other protective mechanisms, the filarial parasite Onchocerca volvulus has a well developed defense system to scavenge toxic free radicals using SODs during migration and sojourning of the microfilariae and adult worms in the human body. O. volvulus is responsible for the neglected disease onchocerciasis or `river blindness'. In the present study, an extracellular Cu/Zn‐SOD from O. volvulus ( Ov EC‐SOD) was cloned, purified and crystallized to obtain structural insight into an attractive drug target with the potential to combat onchocerciasis. The recombinant Ov EC‐SOD forms a dimer and the protein structure was solved and refined to 1.55 Å resolution by X‐ray crystallography. Interestingly, a sulfate ion supports the coordination of the conserved copper ion. The overall protein shape was verified by small‐angle X‐ray scattering. The enzyme shows a different surface charge distribution and different termini when compared with the homologous human SOD. A distinct hydrophobic cleft to which both protomers of the dimer contribute was utilized for a docking approach with compounds that have previously been identified as SOD inhibitors to highlight the potential for individual structure‐based drug development.