BCH3052 Lecture Notes - Lecture 22: G Protein–Coupled Receptor, Chemokine Receptor, Adrenergic Receptor
25 May 2018
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Lecture 22 – Engineering G Protein-Coupled Receptors for Structure
Determination
Goal
• To engineer G protein coupled receptors (GPCRs) so that they can be
crystallized and their 3D structures determined
What are GPCRs?
• Large family of Transmembrane receptors
• Seven hydrophobic regions of ~22 amino acids → form Transmembrane
alpha-helices
o N-terminus: extracellular
o C-terminus: cytoplasmic
• Outside-in-signalling
• Stimulate hetrotrimeric G proteins (alpha, beta and gama)
o Bind to GTP or GDP → causes dissociation of alpha etc. subunits
o Activation of second messenger system
• What GPCR Superfamily are receptors for:
o Ions (calcium sensing)
o Hormones (follicle-stimulating hormones)
o Neurotransmitters (dopamine)
o Odorants (olfactory receptors)
o Pheromones
o Peptides, proteins, light
• Structure of GPCR
o Sequence analysis – on hydrophobicity, and conservation
▪ Formed 7 Transmembrane helices (disulphide bonds)
▪ Cytoplasmic side: 8th helix
▪ 3 loops on extracellular face and 3 loops on intracellular
o Mutagenesis
o Chemical and spectroscopic methods
o Wanted to determine how they interact with
▪ Agonist
▪ Antagonist
▪ Partial agonists
▪ To determine how they signal
o Structure provides:
▪ Insights into ligand recognition
▪ Insights into mechanism of activation
▪ Guidance for drug discovery
GPCRs as Drug Targets
• UP to 50% drug target GPCRs
• Histamine receptors – acid reflux
• Serotonin receptors – depression and enxiety
• Chemokine receptors – inflammation, HIV
• Good drug targets – bind to small molecules → most readily bind to receptors
cell surface (pills)
Adrenergic Receptors
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