8. Approaches to Therapeutics Flashcards
Cytokines can use BLANK different binding interfaces to engage their receptor and stabilise the signalling complex
Cytokines can use 5 different binding interfaces to engage their receptor and stabilise the signalling complex
Site1 Site2 Site3 Stem region JAK-JAK interaction
Protein Engineering Platforms:
Non-cell based methodologies:
- Phage Display
- Ribosomal Display (Leaves stop codon out of genetic template causing the ribosome to pause at the end of the mRNA, providing a complex of mRNA, ribosome, and untranslated protein)
Cell-based methodologies:
- Bacteria Surface Display
- Yeast Surface Display
- Mammalian Surface Display
-Small Molecules Engineering [IS THIS CELL BASED OR NON-CELL BASED?]
IL-2 binds to BLANK
Intracellular JAK phosphorylation of BLANK residues
Via BLANK adaptor, IL-2 causes activation of BLANK pathways
IL-2 binds to IL-2R (IL2Rbeta and gamma-chain)
Intracellular JAK phosphorylation of Tyr residues
Via Shc adaptor, IL-2 causes activation of MAPK pathways
IL-6 family:
Cytokines that use the common signalling receptor subunit GP130
Functions include:
- B cell stimulation
- Stem cell survival
- Induction of the hepatic acute phase proteins
IL-6 exerts its biological activities via binding to 2 molecules:
IL-6Ralpha and GP130
IL-6 signalling:
- IL-6 binds membrane-bound IL-6Ralpha, inducing homodimerisation of GP130
- High affinity hexameric receptor complex of IL-6, IL-6Ralpha, and GP130 is formed
- Formation of hexameric complex results in activation of GP130-associated JAK1 kinases
- JAK1 kinases phosphorylate Tyr residues in cytoplasmic domain of GP130
- pTyr residues recruit the transcription factors STAT1 and STAT3
- TFs are phosphorylated and dimerise
- TF dimers translocate to the nucleus and induce gene expression
Increased/Decreased IL-6 is observed in rheumatoid arthritis
Increased IL-6 is observed in rheumatoid arthritis
IL-10:
IL-10 is a potent immunoregulatory cytokine:
- Inhibits macrophages and dendritic cells
- Activates CD8 T cells
- Decreases inflammation (Decreased IL-12, IL-17, IL-23)
- Increases anti-tumour response (increased IFNgamma))
