Pentamidine blocks the interaction between mutant S100A5 and RAGE V domain and inhibits the RAGE signaling pathway
- Department of Chemistry, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan (China)
The human S100 protein family contains small, dimeric and acidic proteins that contain two EF-hand motifs and bind calcium. When S100A5 binds calcium, its conformation changes and promotes interaction with the target protein. The extracellular domain of RAGE (Receptor of Advanced Glycation End products) contain three domains: C1, C2 and V. The RAGE V domain is the target protein of S100A5 that promotes cell survival, growth and differentiation by activating several signaling pathways. Pentamidine is an apoptotic and antiparasitic drug that is used to treat or prevent pneumonia. Here, we found that pentamidine interacts with S100A5 using HSQC titration. We elucidated the interactions of S100A5 with RAGE V domain and pentamidine using fluorescence and NMR spectroscopy. We generated two binary models—the S100A5-RAGE V domain and S100A5-Pentamidine complex—and then observed that the pentamidine and RAGE V domain share a similar binding region in mS100A5. We also used the WST-1 assay to investigate the bioactivity of S100A5, RAGE V domain and pentamidine. These results indicated that pentamidine blocks the binding between S100A5 and RAGE V domain. This finding is useful for the development of new anti-proliferation drugs. - Highlights: • The interaction between mS100A5–RAGE V was investigated by fluorescence spectroscopy. • The interfacial residues on mS100A5–RAGE V and mS100A5–pentamidine contact surface were mapped by {sup 1}H-{sup 15}N HSQC experiments. • mS100A5–RAGE V and mS100A5–pentamidine complex models were generated from NMR restraints using HADDOCK program. • The bioactivity of the mS100A5–RAGE V and mS100A5–pentamidine complex was studied using WST-1 assay.
- OSTI ID:
- 22606155
- Journal Information:
- Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 2 Vol. 477; ISSN BBRCA9; ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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