Lecture 1- Textures in Ligand Binding

Question 1

Why are receptor-ligand interactions important?

Answer 1

1. Receptors mediate the actions of naturally occuring ligands (hormones, NT, light, odors) and drugs
2. Receptors determin the quantitative relation between concentration of the ligand and pharmacologic effect

• receptor affinity for a ligand determines the concentration of the ligand needed to generate the effect
• # of receptors can limit the max effect a drug might have

3. Receptors are responsible for how selective drugs act

• shape, size, charge of a ligand determines IF and the AFFINITY a ligand will bind a receptor/specific site of a receptor of all the available ones in the cell
• changes in the ligand chemical structure can increase or decrease the affinity for a receptor –> this can result in alterations of therapeutic or toxic effects

Question 2

Ligands can…

Answer 2

1. Can be intrinsic to a receptor
   * cleavage needed to activate it
2. Need a trigger to become active

• already present in the receptor
• needs to get activated to induce its response

3. Come from other cells

• need to travel a certain distance
• bloodstream
• ex: hormones: produced by organs somewhere, trafficked in blood, reaches target

Question 3

Class C GPCRs

Answer 3

• Sushi domain creates disulfide bonds required to maintain tertiary structure: keeps a binding site alive!
• For GPCRS, multiple classes
• 7 transmembrane domains, integrated in PM
• different extracellular domains can be present on a receptor
• has long tails on outside of cell, that is what catches the ligand
• two domains that are like pacmans: catch a ligand
• thats where ligand binds

Class C GPCRS: ligands bind in extracellular portion

• Variability among receptors even if there in same class

Question 4

Class A GPCR

Answer 4

• Structure of b2ar and rhodopsin with 2 ligands in them.
• 2 different structures shown
• could be seen as a snake or a barrel
• creates hole in the middle
• hole in middle (red) where the ligand binds to the receptor
• To activate them, ligands need to penetrate into the barell

Question 5

Diversity among extracellular domains affect ligand binding capacities

Answer 5

• Long tail, may be masking the hole
• Based on diff receptors, will have different affinities for the ligand to bind that place/receptor

Question 6

Do different structures bind the same receptor?

Answer 6

Although different structures for those ligands, all bind the same receptor, but bind at different sites

• binding at one site on receptor, has a ripple effect all across the receptor à differences in efficacy
• bind ligand at one part, may be able to bind a little bit more or less of ligands
• ligand pulls at one site, another ligand pulls at another site
• gives you different efficacy for that receptor

Question 7

Shape, size, and charges all play a role that shapes where the ligand will bind

Answer 7

• Different a.a lining the binding pocket of that receptor
• attraction and repulsion
• If it attracts, frees up one side
• Get first, second touch –> shapes and creates a stable conformation in the end
• Movement of transmembrane domains and a.a, even the ligand flips sometimes

Question 8

How do we get receptor activation

Answer 8

• disruption of the ionic lock
• EX: Ripple effect from binding of ligand à conformational change that rotates the glutamine, allows the receptor to open up and have a shape to where it gets activated

Question 9

The rhodopsin receptor model

Answer 9

• If the crystals are grown upside down in a strong magnetic field, fluid flows that disrupt crystal growth are suppressed.

Rhodopsin

• green= ligand, always present in receptor
• In dark, get a kink: 11-cis retinal holds transmembrane regions in the inactive conformation
• rhodopsin exposure to light, get conformational change in retinal that allows it to become straight, changes the conformation of the receptor
• Allows the revealing of sites that were not exposed previously

Question 10

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