3.2

Question 1

What are the major types of interactions between GPCR amino acids?

Answer 1

Hydrophobic, electrostatic, hydrogen bonds, disulfide bridges.

Question 2

What makes transmembrane α-helices (TMs) amphipathic?

Answer 2

They have both hydrophobic and hydrophilic surfaces.

Question 3

Which residues can be phosphorylated in GPCRs?

Answer 3

Serine (Ser), Threonine (Thr), and Tyrosine (Tyr).

Question 4

What is the structural role of cysteines in GPCRs?

Answer 4

They form disulfide bridges anchoring extracellular domains.

Question 5

Where do Class A GPCR ligands typically bind?

Answer 5

Upper transmembrane domain (TMD) and/or extracellular domain (ECD).

Question 6

Where is the orthosteric site for Class B GPCRs?

Answer 6

Both ECD and TMD.

Question 7

How is Class C GPCR ligand binding unique?

Answer 7

Ligands bind to a Venus flytrap (VFT) module in the ECD.

Question 8

What domain do Wnt ligands bind in Frizzled (FZD)?

Answer 8

The cysteine-rich domain (CRD) in the ECD.

Question 9

How does ligand binding lead to signalling?

Answer 9

Through allosteric interaction networks that transmit changes from the ligand binding site to the cytosolic face.

Question 10

What is the shared activation feature across GPCR classes?

Answer 10

Outward movement of TM6 to allow G protein binding.

Question 11

What structural motifs mediate Class A GPCR activation?

Answer 11

CWxP, PIF, DRY motif (“ionic lock”), Na+ pocket, NPxxY.

Question 12

What is the role of the DRY motif?

Answer 12

Forms an “ionic lock” with TM6 to stabilize the inactive state.

Question 13

What structural changes occur upon activation?

Answer 13

TM6 moves outward; TM3-TM7 and TM3-TM6 interactions are altered.

Question 14

What residues are conserved for stabilisation?

A

Answer 14

Cysteines in ECD and prolines in TM5–7 (create kinks for flexibility).

Question 15

What is β2AR coupled to?

Answer 15

Gs protein.

Question 16

What physiological effects does β2AR mediate?

Answer 16

Bronchodilation, vasodilation, smooth muscle relaxation, glycogenolysis.

Question 17

Name one β2AR agonist and its use.

Answer 17

Salbutamol – for asthma.

Question 18

Name one β2AR antagonist and its use.

Answer 18

Propranolol – for hypertension.

Question 19

What key residues bind orthosteric ligands in β2AR?

Answer 19

D113, N312, S203, S207 (H-bonds), plus hydrophobic contacts.

Question 20

What is the first structural step after agonist binding?

Answer 20

Rearrangement of TM5 via serines → hydrophobic network shift.

Question 21

What structural motif collapses next?

A 2nd

Answer 21

Na+ pocket collapses → TM7 moves toward TM3.

Question 22

What happens after TM7 moves?

Answer 22

NPxxY rewires → TM6 loosens and moves outward.

Question 23

What is the final step before G protein binding?

Answer 23

The ionic lock breaks → Gα binding pocket opens (lined by TM3, 5, 6).

Question 24

What is the binding sequence for Class B peptide hormones?

Answer 24

First: ECD binds peptide C-terminus; Second: N-terminus inserts into TMD.

Question 25

What stabilises the inactive state of Class B GPCRs?

Answer 25

Polar core interactions and ECD-TMD contacts.

Question 26

What motifs stabilise the active state? | B

Answer 26

NPGQ motif; facilitates large TM6 movement (~20Å).

Question 27

What structural feature is unique to Class C GPCRs?

Answer 27

VFT domain (Venus Flytrap module) in the ECD.

Question 28

How do Class C GPCRs activate?

Answer 28

Ligand closes VFT → induces TMD rearrangement → TM6 interface forms.

Question 29

What conserved motifs support activation? | C B

Answer 29

Ionic lock (inactive), FxxCWxP (couples ligand to TM6), FxPKxY (active state stabiliser).

Question 30

What is constitutive activity?

Answer 30

Basal receptor signalling without ligand.

Question 31

What does an inverse agonist do?

Answer 31

Reduces receptor activity below basal level.

Question 32

How do inverse agonists differ from antagonists?

Answer 32

Antagonists block activation to basal; inverse agonists reduce activity below basal.

Question 33

What residues are involved in β2AR ligand binding?

Answer 33

D113, N312, S203, S207 (agonist-specific H-bonds); hydrophobic core.

Question 34

How do inverse agonists bind differently than agonists?

Answer 34

Fewer polar contacts with TM5; stabilize inactive conformations.

Question 35

How does the intracellular pocket differ by ligand?

Answer 35

Agonists induce large pockets (450–950 ų), inverse agonists much smaller (~100 ų).

Question 36

How does water content vary with binding?

Answer 36

Agonists have more water (~23), inverse agonists have less (~14).

Question 37

What is biased signalling?

Answer 37

Ligand-specific stabilization of receptor conformations that favour distinct effectors.

Question 38

What drives biased signalling?

Answer 38

Different ligands shift allosteric networks to favour Gαs, Gαi, Gαq, or β-arrestin pathways.

Question 39

What movement is favoured in Gαs vs β-arrestin bias?

Answer 39

Gαs: greater TM6 movement; β-arrestin: TM7 shift.

Question 40

What is allosterism in GPCRs?

Answer 40

Ligand binding at non-orthosteric site modulates receptor function.

Question 41

What are types of allosteric modulators?

Answer 41

PAMs (positive), NAMs (negative), and neutral ligands.

Question 42

Do allosteric modulators have intrinsic efficacy?

Answer 42

No – they only affect orthosteric ligand function.