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PHAR2005 > Receptor structure > Flashcards

Receptor structure Flashcards

1
Q

What is the definition of a receptors ?

A

Receptors = Proteins that are the site of action of neurotransmitters, hormones, growth factors and other inter-cellular (cell-to-cell) signalling molecules.

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2
Q

What are the 4 structurally distinct families of receptors ?

A

1) Ligand-gated ion channels (LGICs) (e.g. nAChR)
2) G-protein-coupled receptors (GPCRs) (e.g. mAChR)
3) Kinase-linked and related receptors (e.g. insulin receptor)
4) Nuclear receptors (e.g. oestrogen receptor)

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3
Q

What are other names for LGICs ?

A
  • agonist-activated ion channels
  • neurotransmitter-gated ion channels
  • ionotropic receptors
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4
Q

What are LGICs ?

A
  • LGICs are multi-subunit (oligomeric) transmembrane proteins that contain an integral ion channel
  • The LGIC family includes receptors for several neurotransmitters
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5
Q

Give examples of NTs and the receptors they bind to.

A 
ACh --> nAChR
5-hyroxytryptamine (5-HT) --> 5-HT3R
GABA --> GABA(A) R
Gly --> GlyR
Glu --> GluR
ATP --> ATP (P2X) receptor
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6
Q

How many subunits can LGICs contain ?

A

3, 4 or 5.

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7
Q

What effects do excitatory Vs inhibitory LGICs have ?

A

LGIC receptors are either :

  • excitatory cation (e.g. Na+) channels (which cause membrane depolarisation) = receptor for Ach, 5-HT, Glu and ATP
  • inhibitor anion (e.g. Cl-) channels (causing membrane hyperpolarisation) = GABA and Gly
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8
Q

Give examples of trimeric, tetrameric and pentameric LGICs.

A

Trimeric : ATP (P2X)Rs
Tetrameric : GluRs
Pentameric : nAChRs, GABA(A)Rs, GlyRs, 5-HT3Rs

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9
Q

What are “Cys loop” receptors ?

A

“Cys-loop” receptor are receptors that possess a characteristic loop formed by 13 highly conserved amino acids between two cysteine (Cys) residues which form a disulfide bond, near the N-terminal extracellular domain.

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10
Q

When are nAChRs expressed in mammals ?

A

Nicotinic receptors are expressed at the mammalian

neuromuscular junction and within the central and peripheral nervous system.

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11
Q

In what organism in particular are nAChRs expressed ?

Why was this important for early research on nAChRs ?

A

nAChRs are also expressed (at high density) in the electric organ of fish such as the marine ray Torpedo.
This abundant source of receptor is a major reason why the Torpedo nAChR was the first neurotransmitter receptor to be purified and cloned.
Three dimensional structural information has been obtained for the nAChRs expressed in Torpedo.
This was achieved by cryo-electron microscopy of tubular crystals of Torpedo post-synaptic membrane.

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12
Q

What subunits make up the torpedo nAChRs ?

A

alpha-2-beta-gamma-delta (a2bgd)

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13
Q

What conformational change is there when the nAChR flips from an open to a closed state ?

A

The structure of the Torpedo nAChR has also been determined in both its open and closed conformations. This has provided evidence for a change in conformation of alpha-helices lining the membrane-spanning pore.

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14
Q

What conformational change happens when the GluR flips from an open to a closed state ?

A

The GluR is ~ 180 Å long, and switches from a 150 Å width to a 90 Å width by a 90 degree turn.

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15
Q

What are other names for GPCRs ?

A
  • Seven-transmembrane (7TM) receptors
  • Heptahelical receptors
  • Metabotropic receptors
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16
Q

What are GPCRs ?

A 
GPCRs are a very large and diverse receptor super-family which contains > 1000 different receptor subtypes and are the largest family of transmembrane receptors
This family includes receptors for:
- Neurotransmitters
- Neuropeptides
- Peptide hormones
- Glycoprotein hormones
- Odorants
17
Q

How do GPCRs work ?

A

GPCRs mediate intracellular signalling via interaction with intracellular G-proteins (heterotrimeric proteins which catalyse the interconversion of guanine nucleotides, GTP and GDP).
G-proteins activate or inhibit various enzymes such as
AC and PLC and thereby modulate the synthesis of second messengers such as cAMP and IP3.
G-proteins can also act by modulating the function of ion channels.

18
Q

What different types of GPCRs are there ?

A
  • mAChRs
  • metabotropic GluRs
  • 5-HT Rs
  • GABA Rs
  • DARs
  • ADRs
19
Q

What common structural feature do all GPCRs share ?

A

Common structural features include an extracellular N-terminus, an intracellular C-terminus and 7 alpha-helical transmembrane domains.

20
Q

Do GPCRs exist as monomers or dimers ?

A

Evidence indicates that several GPCRs exist as
dimers (either homo-dimers or hetero-dimers).
For example, GABA(B) R1 fails to form a functional cell-surface receptor unless as a dimer with GABA (B) R2.

21
Q

When was the 1st GPCR crystal structure obtained ?

A

The first crystal structure of a GPCR (rhodopsin, a light-

sensing protein) was determined in 2000 and revealed a structure with seven transmembrane helices.

22
Q

When was the 1st ligand binding GPCR crystal structure obtained ?

A

2007 –> the B-2 ADR

23
Q

When was the 1st ligand binding GPCR bound to a cytoplasmic heterotrimeric G-protein crystal structure obtained ?

A

2001 –> the B-2 ADR coupled to a cytoplasmic heterotrimeric G-protein

24
Q

What are kinase linked (and related) receptors ?

A

Act as receptors for a wide range of signalling molecules (all of which are peptides) including peptide hormones
(e.g. insulin), growth factors (e.g. epidermal growth factor) and cytokines (eg. interleukins).

25
Q

Give examples kinase linked and related receptors, along with their ligands ?

A

Tyrosine kinase receptors : Insulin, epidermal growth factor
Tyrosine kinase-linked receptors : Growth hormone
Serine/threonine kinase receptors : Transforming growth factor
Guanylate cyclase receptors : Atrial natriuretic peptide

26
Q

What is the structure of KLRs ?

A
  • Extracellular ligand-binding domain
  • Single transmembrane domain
  • Intracellular effector domain
27
Q

Give an example of nuclear receptors.

A

Steroid hormone receptors.

28
Q

What are the characteristics of nuclear receptors ?

A

Soluble, rather than transmembrane receptors.

Regulate gene transcription.

29
Q

How do nuclear receptors work ?

A

Binding of ligand (e.g. steroid hormone) promotes the formation of receptor dimers.
The dimeric, ligand-bound receptor is able to act as a
transcription factor by binding to specific regions of genomic DNA (hormone-responsive elements).

30
Q 
Atomic resolution (X-ray diffraction) crystal structures of the ligand-binding domain. 
What is the key conformational difference between the oestrogen/estrogen receptor bound with an agonist (estradiol) or antagonist (raloxifene).
A

The movement of the H12 helix (downward movement with agonist, upward movement with antagonist).

PHAR2005 (24 decks)

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