Crystal structure of N-terminally hexahistidine-tagged Onchocerca volvulus macrophage migration inhibitory factor-1

Area of Science:

• Structural Biology
• Parasitology
• Drug Discovery

Background:

• Onchocerca volvulus causes river blindness, onchocerciasis, and neurological diseases.
• Current treatments like ivermectin have contraindications for pregnant women and Loa loa co-infections.
• Novel drug targets are crucial for effective onchocerciasis treatment.

Purpose of the Study:

• To determine the apo structure of N-terminally hexahistidine-tagged Onchocerca volvulus macrophage migration inhibitory factor-1 (His-OvMIF-1).
• To investigate OvMIF-1 as a potential drug target for onchocerciasis.
• To characterize the structural features of OvMIF-1, including its unique C-terminal tail.

Main Methods:

• Production and purification of N-terminally hexahistidine-tagged OvMIF-1.
• Crystallization and X-ray diffraction for structure determination.
• Size-exclusion chromatography and PISA analysis to assess oligomeric state.

Main Results:

• The apo structure of His-OvMIF-1 was determined, revealing a unique jellyfish-like conformation.
• OvMIF-1 possesses a distinct C-terminal tail contributing to its structure.
• Removal of the N-terminal tag exposes a larger cavity, suggesting potential for drug repurposing.
• Oligomeric state determination was complex, with size-exclusion suggesting a monomer and PISA suggesting a hexamer.

Conclusions:

• OvMIF-1 is a promising drug target for onchocerciasis, with a structure amenable to drug discovery.
• Further studies are needed to resolve the oligomeric state of OvMIF-1 for precise drug targeting.
• Structural insights into OvMIF-1 pave the way for developing new treatments against river blindness.