Cell Signalling IV

Question	Answer
Enzyme linked receptors	Tyrosine Kinase Receptors (TKRs)
TKRs	1. EXC domain binds ligand. 2. Transmembrane domain 3. IC domain, has TK 4. +Pi Tyr residues from ATP
PK casses	TK serine/threonine kinases e.g. PKA/B/C
Binding to PK	1. Ligand binds to monomer 2. Induces conf. Δ in EC dom., dimerise 3. Induces conf. Δ in IC domain. 4. Auto-Pi,reveals substrate BS on opposite R 5. Transphosphorylation. 6. +Pi-Tyr provides docking site for signalling molecule.
GF R signalling	+Pi -> Grb2 -> SOS -> Ras GTP
Insulin R signalling	1. Unusual as adaptors are +Pi by receptor themselves. 2. +Pi on IRS provide docking sites for a multitude of signalling cascades. 3. Compensatory mechanism as Insulin R doesn't have many Tyr in IC domain. (extension cord).
Ras	Monomeric G protein (acts like alpha SU) + When bound to GTP Intrinsic GTPase activity to - Accessory proteins required to cycle between +/-
+/- of Ras	GEFs -> + GAP -> - (Cycle)
Ras signal cascade	Ras Y-Pi -> Grb2 -> SOS -> Ras-GDP -> Ras-GTP -> MEK _MAPK -> +Pi-TF Ras-GDP -> Ras-GTP (SOS) Ras-GTP -> Ras-GDP (GAP)
Insulin Receptor	Only TK to not dimerise Heterotetrameter in PCM Alpha SU bind to insulin Induces conf. Δ in TK -> trans/auto+Pi
Insulin R cascade	Insulin -> Alpha -> trans/auto-> IRS-1 -> PIP2 -> PIP3 -> PDK1 -> PKB -> Glut-4 vesicle translocation
Why do this?	Regulates glucose uptake Vesicle translocates to PCM, fuses, takes up glucose, passes it back into cell.
Enzyme -linked R	Recruit EZ from cytoplasm e.g. Cytokine R recruit JAK to help initiate cell signalling
MOA (6)	1. Cytokine R lacks intrinsic K activity. 2. Recruit soluble TK i.e. JAK. 3. Ligand binding causes R dimerisation + JAK+ 4. JAK + each other and R 5. Adaptor proteins recruited to +Pi-Tyr on R OR 6. STAT TF directly to JAK
Preferable drug design	Small molecules favoured
The protein	domains capable of strong+specific interactions w/ drug Has cavity e.g. well defined catalytic cleft
Good/Bad targets?	Good: R/EZ Bad: TF (apart from Nuclear R's).
Common target	Competitive binding to ATP binding region to prevent gamma-phosphorylation
Nuclear Receptors	Ligand + TF
Domain Structure:	Mod. conserved ligand-binding dom. Highly conserved DNA binding dom. Highly variable N-term w/ 1(>) + Domains
Categorisation 1 based on MOA and distribution in cell when L absent (5)	Category 1: Steroid/androgen R. Found in cyto associated w heat shock protein Forms a homodimer Once in nucleus recruits co-+'s to mod. chromatin/DNA Pol' activity.
Category 2	In nucleus Sit on response cell event (DNA) Form heterodimer, always complexed to RxR Core repressor keeps chromatin compact, preventing gene transcription.
Category 2 diagram	Yoooohohoho
Anti-hormone drugs	e.g. Tamoxifen Struct similar to hormone, binds to LBD Allows R dimerisation + binding to DNA/gene promoter Side chains rpevent correct structural rearrangement of R Co-activator BS is BLOCKED.

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	Created by J yadonknow over 6 years ago