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Structural Analysis of an Epitope Candidate of Triosephosphate Isomerase in Opisthorchis viverrini
Jonghyeon Son1, Sulhee Kim1, So Eun Kim1
1Division of Biotechnology, College of Life Sciences & Biotechnology, Korea University, Seoul, 136-701, South Korea.
Abstract:
Opisthorchis viverrini, a parasitic trematode, was recategorized as a group 1 biological carcinogen because it causes opisthorchiasis, which may result in cholangiocarcinoma. A new strategy for controlling opisthorchiasis is needed because of issues such as drug resistance and reinfection. Triosephosphate isomerase (TIM), a key enzyme in energy metabolism, is regarded as a potential drug target and vaccine candidate against various pathogens. Here, we determined the crystal structures of wild-type and 3 variants of TIMs from O. viverrini (OvTIM) at high resolution. The unique tripeptide of parasite trematodes, the SAD motif, was located on the surface of OvTIM and contributed to forming a 310-helix of the following loop in a sequence-independent manner. Through thermal stability and structural analyses of OvTIM variants, we found that the SAD motif induced local structural alterations of the surface and was involved in the overall stability of OvTIM in a complementary manner with another parasite-specific residue, N115. Comparison of the surface characteristics between OvTIM and Homo sapiens TIM (HsTIM) and structure-based epitope prediction suggested that the SAD motif functions as an epitope.
Insights
Opisthorchis viverrini triosephosphate isomerase (OvTIM) has a unique surface motif (SAD) that may serve as a drug target. This finding offers a new strategy for controlling opisthorchiasis, a disease linked to cancer.
Area of Science:
- Parasitology
- Structural Biology
- Biochemistry
Background:
- Opisthorchis viverrini is a biological carcinogen causing opisthorchiasis and cholangiocarcinoma.
- Drug resistance and reinfection necessitate novel control strategies for opisthorchiasis.
- Triosephosphate isomerase (TIM) is a crucial metabolic enzyme and a potential drug/vaccine target.
Purpose of the Study:
- To determine the high-resolution crystal structures of wild-type and variant O. viverrini TIM (OvTIM).
- To investigate the structural role and stability contributions of the unique surface SAD motif in OvTIM.
- To explore the potential of the SAD motif as a target for therapeutic intervention.
Main Methods:
- High-resolution X-ray crystallography of OvTIM wild-type and variants.
- Thermal stability assays.
- Structural analysis and comparison with Homo sapiens TIM (HsTIM).
- Structure-based epitope prediction.
Main Results:
- The crystal structures of OvTIM and three variants were determined.
- A unique surface tripeptide motif (SAD) forms a 310-helix in a sequence-independent manner.
- The SAD motif, along with residue N115, influences OvTIM's local surface structure and overall stability.
- Structural comparison and epitope prediction suggest the SAD motif is a potential B-cell epitope.
Conclusions:
- The SAD motif is a parasite-specific structural feature of OvTIM.
- The SAD motif plays a role in OvTIM stability and surface structure.
- OvTIM's SAD motif is a promising target for developing new anti-parasitic drugs or vaccines against opisthorchiasis.
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