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HIF-1α and RKIP: a computational approach for pancreatic cancer therapy
Gowru Srivani1, Santosh Kumar Behera2, Begum Dariya1
1Department of Bioscience and Biotechnology, Banasthali University, Vanasthali, Rajasthan, 304022, India.
Abstract:
Protein-protein interactions (PPIs) are important biochemical processes that represent a major challenge in modern biology. Current approaches, which include high-throughput screening and computer aided ligand design, have limitations regarding the identification of hit matter. This current investigation focuses on computational study for protein-protein docking of hypoxia inducible factor-1α (HIF-1α), a tumor inducible factor, and Raf-1 kinase inhibitory protein (RKIP), a tumor metastasis suppressor. These are individually crystallized structures of interacting proteins, which interact to generate a conformational space. HIF activity in pancreatic tumors is determined by hypoxia and HIF-1α subunit availability. RKIP can be used as a prognostic indicator in a number of tumors. The interaction of RKIP with HIF-1α protects against pancreatic cancer (PC) metastasis by inhibiting its hypoxia function. We have explored the binding affinity between both the proteins with the HADDOCK (high ambiguity driven protein-protein docking) server, which determined that 158 structures in 11 clusters represent 79.0% of water-refined models. Of the best 10 clusters, the structures of cluster 2 were found to be better, as they had the lowest Z-score. Further supporting HIF-1α-RKIP interaction, pulldown assay has shown dissociation of RKIP from HIF-1α after CoCl2 treatment in both PC cell lines.
Insights
This study computationally investigated the interaction between hypoxia-inducible factor-1α (HIF-1α) and Raf-1 kinase inhibitory protein (RKIP). Their binding is crucial for inhibiting pancreatic cancer metastasis by blocking HIF-1α's hypoxia function.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Protein-protein interactions (PPIs) are vital but challenging to study.
- Hypoxia-inducible factor-1α (HIF-1α) drives tumor growth, while Raf-1 kinase inhibitory protein (RKIP) suppresses metastasis.
- RKIP's interaction with HIF-1α inhibits hypoxia-driven pancreatic cancer (PC) metastasis.
Purpose of the Study:
- To computationally investigate the protein-protein docking between HIF-1α and RKIP.
- To analyze the binding affinity and structural basis of the HIF-1α-RKIP interaction.
- To understand the role of this interaction in pancreatic cancer progression.
Main Methods:
- High-ambiguity driven protein-protein docking (HADDOCK) server was utilized for computational docking.
- Analysis of water-refined models and cluster structures to identify optimal binding poses.
- Pulldown assays were performed to validate the interaction in pancreatic cancer cell lines.
Main Results:
- HADDOCK identified 158 structures in 11 clusters, with cluster 2 showing the best binding affinity (lowest Z-score).
- The computational models suggest a specific binding mode between HIF-1α and RKIP.
- Pulldown assays confirmed the HIF-1α-RKIP interaction and its dissociation upon CoCl2 treatment in PC cell lines.
Conclusions:
- The study computationally validates the interaction between HIF-1α and RKIP.
- This interaction plays a significant role in suppressing pancreatic cancer metastasis.
- Targeting the HIF-1α-RKIP interaction could offer a therapeutic strategy for pancreatic cancer.
