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Questions and Answers
What is the main mechanism by which a drug or hormone signal is transmitted into the cell via GPCRs?
G Protein
How many transmembrane helices do all GPCRs have in common?
7
What distinguishes Family A GPCRs from Family B GPCRs in terms of their structure?
Family A do not typically have an extracellular domain, while Family B GPCRs do.
What is the study of how individual genetic differences can influence how drugs work through receptors called?
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What must be done to study GPCRs, considering their microenvironment and structure?
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Where is the orthosteric binding pocket located in the Beta 2 Adrenergic Receptor?
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What is the main role of Beta 2 Adrenergic receptors in heart failure?
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How does Propranolol act on Beta 2 Adrenergic receptors?
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Explain the concept of GPCR cross reactivity.
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What is drug repositioning/repurposing in the context of GPCRs?
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Describe the role of glycosylation in proteins.
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What are the three subunits that make up a G protein?
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What percentage of disease states concerning membrane proteins are accounted for by mutations in the conserved amino acids?
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What is the role of cholesterol in GPCR function?
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How do mutations in a conserved Tryptophan affect GPCRs?
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Explain the concept of allosteric regulation in GPCRs.
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Study Notes
G Protein-Coupled Receptors (GPCRs)
- GPCRs are a collective term for membrane proteins that share a common mechanism of signaling
- They have a common structure, with 7 transmembrane helices
- Approximately 800 different GPCRs exist in humans, divided into classes (e.g., Family A and Family B)
- Family A GPCRs typically lack an extracellular domain, whereas Family B GPCRs have an extracellular domain
Function and Mechanism
- A drug or hormone binds to a GPCR, and the signal is transmitted into the cell via a G Protein
- The signal is transmitted through a mechanical conformational shape change in the receptor
- This allows recruitment of a G protein at the intracellular side, which is composed of 3 subunits (alpha, beta, and gamma)
Microenvironment and Post-Translational Modifications
- The microenvironment of GPCRs influences their function (e.g., lipids surrounding the receptor and interacting proteins)
- Glycosylation (addition of sugars) and disulfide bonds (between cysteine amino acids) are important for GPCR structure and function
Orthosteric Binding Site and Conformational Change
- The orthosteric binding site is the main binding site for the ligand, located in the transmembrane helix
- The binding of a ligand induces a conformational change, allowing recruitment of the G protein
Disease and Mutations
- Mutations to conserved amino acids in the center of the receptor account for 87% of disease states concerning membrane proteins
- Mutations can either stop signal transmission, increase sensitivity, or cause constitutive activity
Cholesterol Binding and Allosteric Regulation
- All GPCRs have a specific cholesterol binding site located on the external surface of the receptor
- Cholesterol binding is necessary for GPCR function; without it, receptors may activate spontaneously or not operate at all
- Allosteric regulation of GPCRs by cholesterol modulates the function of the orthosteric pocket
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Description
Explore the world of G Protein Coupled Receptors, a group of membrane proteins sharing a common signaling mechanism. Learn about how drugs and hormones bind to GPCRs to transmit signals into cells via G Proteins, and understand the common structural features of GPCRs with 7 transmembrane helices.
