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G Protein Coupled Receptors (GPCRs)

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16 Questions

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?

Pharmogenomics

What must be done to study GPCRs, considering their microenvironment and structure?

Purify them using detergents to solubilize them

Where is the orthosteric binding pocket located in the Beta 2 Adrenergic Receptor?

⅓ of the way into the transmembrane helix (extracellular half of the receptor)

What is the main role of Beta 2 Adrenergic receptors in heart failure?

Involved in heart failure

How does Propranolol act on Beta 2 Adrenergic receptors?

Blocks the Beta 2 Adrenergic receptor

Explain the concept of GPCR cross reactivity.

Similar orthosteric location in the receptor

What is drug repositioning/repurposing in the context of GPCRs?

Using existing drugs to treat different disease states

Describe the role of glycosylation in proteins.

Adding sugars onto the protein to protect it

What are the three subunits that make up a G protein?

Alpha, beta, gamma

What percentage of disease states concerning membrane proteins are accounted for by mutations in the conserved amino acids?

87%

What is the role of cholesterol in GPCR function?

Specific cholesterol binding site on the external surface of the receptor

How do mutations in a conserved Tryptophan affect GPCRs?

Responsible for various conditions like dementia and certain cancers

Explain the concept of allosteric regulation in GPCRs.

Modulating receptor function by binding to sites other than the orthosteric pocket

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

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.

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