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Introduction

  • The direct effects of drugs on cellular function generally lead to secondary, delayed effects, which are often very important to therapeutic efficacy and harmful effects
  • The “Drug + Target” combination leads to:
    1. Rapid physiological responses [which can slowly lead to 2) ]
    2. Altered gene expression
      • This leads slowly to delayed responses

Explanation:

  • Many drugs act directly on their targets to produce an immediate physiological response
  • If a physiological response is maintained, it is likely to cause changes in gene expression, producing delayed physiological responses
  • Drugs can also work by both pathways

Targets for drugs action

The protein targets for drug action on mammalian cells are divided into:

  1. Receptors
  2. Ion channels
  3. Enzymes
  4. Carrier molecules (transporters)

Receptors

  • Receptors are the sensing elements in the system of communications that coordinates the function of all the different cells in the body.
  • Hormones, transmitters and other mediators are the chemical messengers.
  • Many therapeutically useful drugs act (either as agonists or antagonists) on receptors for known endogenous mediators.

Ion channels

  • Ligand-gated ion channels (or ionotropic receptors) have a receptor, and they will only open if the receptor is occupied by an appropriate agonist
  • There are other types, for example Voltage-gated ion channels (see later)
  • Drugs can affect ion channel function by interacting with:
    • The receptor site of ligand-gated ion channels
    • Other parts of the channel molecule
  • This interaction can be:
    • Indirect - Via a G-protein and other intermediaries
    • Direct - Where the drug itself binds to the channel protein and alters its function
  • Example:
    • Local anaesthetics are drugs that physically plug the channel of voltage-gated ion channels, preventing ion permeation

Enzymes

  • Drugs can be targeted on enzymes. Various possibilities
    • Competitive: The drug molecule is a substrate analogue that acts as a competitive inhibitor of the enzyme
    • Non-competitive: The binding between the drug and the enzyme is irreversible and non-competitive
    • False Substrates: The drug molecule undergoes chemical transformation to form an abnormal product that subverts [undermines] the normal metabolic pathway
  • Pro-drugs: are inactive molecules that require conversion by an enzyme to make them into the active form of the drug
  • Toxicity often results from enzymic conversion of drugs into reactive metabolites (this is one way that side effects can occur)

Carrier molecules

  • The transport of ions and small organic molecules across cell membrane (normally) requires carrier proteins.
    • The permeating molecules are often too polar (and lipid insoluble; lipophobic) to penetrate lipid membranes
    • Carrier proteins are a recognition site that makes them specific for a particular permeating species, and these recognition sites can also be targets for drugs whose effect is to block the transport system
  • Many examples of proteins that transport:
    • Glucose and amino acids
    • Ions and organic molecules (in the renal tubules)
    • Na+ and Ca2+ out of cells
    • [Uptake of] neurotransmitters or their precursors by nerve terminals
  • Symport and antiport
    • The transport of organic molecules is usually coupled to the transport of ions (usually Na+):
      • Symport: organic molecules and ions are transported in the same direction across the membrane
      • Antiport: organic molecules and ions are transported in opposite directions across the membrane

Receptor proteins

Isolation and cloning of receptors

  • Introduce the cloned DNA encoding individual receptors into cell lines, producing cells that express the foreign receptors in a functional form
  • This allowed more precise control of the expressed receptors than is possible in natural cells or tissues and revelead many molecular variants of known receptors.

Receptor heterogeneity and subtypes

  • Receptors within a given family generally occur in several molecular varieties (or subtypes) with similar 3D structure but very different sequences. Often they also commonly have very different pharmacological properties.
    • This diversity arises from
      1. Different genes coding for the different subtypes
      2. Alterntive mRNA splicing, so that a single gene can produce more than one receptor isoform [due to variations in the sizes of exons coding for the protein that produces various lengths of protein. This can result in GPCRs with various binding characteristics and signal transduction mechanisms]
      3. mRNA editing
  • This molecular heterogeneity produces an amazing plethora of subtypes of receptors, and a nightmare of classification.

Types of receptor

Type 1: Ligand-gated ion channels (aka ionotropic receptors)

  • Channels that incorporate a ligand-binding (receptor) site, usually in the extracellular domain
  • These are typically the receptors on which neurotransmitters act
  • Molecular structure:
    • At the bottom of this section is the nicotinic acetylcholine receptor
    • Made up of 4 different types subunits: alpha, beta, gamma and delta
    • Two alpha subunits are present, along with 1 of each of the other kinds of subunit
    • This pentameric structure has two binding sites for acetylcholine
    • Each binding site lies in between one of the two alpha subunits and its neightbour
    • Both binding sites must bind acetylcholine (ACh) in order to activate the receptor
    • Each subunit spans the membrane 4 times, so the channel comprises 20 membrane-spanning helices surrounding a central pore.
    • The two ACh binding sites lie on the extracellular parts of the 2 alpha-subunits
    • One of the transmembrane helices (M2) from each of the 5 subunits forms the lining of the ion channel
    • The five M2 helices that form the pore are sharply kinked inwards halfway through the membrane, forming a constriction
    • ACh binds --> alpha-subunits twist --> the kinked M2 segments swivel out of the way, opening the channel
    • Lots of ligand-gated ion channels have a similar structure to this one and have similar homology to this nicotinic acetylcholine receptor. (Usually 4 or 5 subunits make up a functional receptor)
    • Some ligand-gated ion channels have a different 3D structure:
      • The pore is build from loops rather than transmembrane helices
      • This is common with many other (non ligand-gated) ion channels
  • The gating mechanism
    • LGICs control the fastest synaptic events in the nervous system: a neurotransmitter acts on the postsynaptic membrane of a nerve or muscle and transiently increases its permeability to particular ions
      • Na+ influx due to neurotransmitter stimulating an LGIC
    • Acetylcholine at the NMJ, or glutamate in the CNS cause an increase in Na+ and K+ permeability, so there is an inward current carried (mainly) by Na+, which depolarises the cell and increases the probability that it will generate an AP.
    • Very Fast: the action of the transmitter reaches a peak in a fraction of a millisecond, then decays in a few milliseconds. This is due to the direct coupling between the receptor and the ion channel [see the diagram of the molecular structure of the receptor-channel complex]
    • No intermediate biochemical steps are involved in the transduction process
    • Very high current can pass through, since there is a physical pore rather than a carrier mechanism
  • Patch clamp recording technique
    • Neher and Sakmann
    • Allows us to directly measure the very small current flowing through a single ionic channel.
    • Shows us the behaviour of individual protein molecules in real time
    • Shows us the gating reactions and permeability characteristics of both ligand-gated channels and voltage-gated channels
    • Many agonists cause individual channels to open to one or more of several distinct conductance levels… there are different receptor conformations associated with different channel conductances (not just a single R*).
    • Along with desensitisation, this shows that our model of a single open state (R*) is a little weak

Summary:

  • These are sometimes called ionotropic receptors.
  • They are involved mainly in fast synaptic transmission.
  • There are several structural families, the commonest being heteromeric assemblies of four or five subunits, with transmembrane helices arranged around a central aqueous channel.
  • Ligand binding and channel opening occur on a millisecond timescale.
  • Examples include the nicotinic acetylcholine, GABA type A (GABAA), and 5-hydroxytryptamine type 3 (5-HT3) receptors.

Type 2: G-protein-coupled receptors (GPCRs) (a.k.a. metabotropic receptors or 7-transmembrane-spanning (heptahelical) receptors)

  • Membrane receptors that are coupled to intracellular effector systems via a G-protein
  • Abundant
  • Include receptors for hormones and slow transmitters, e.g. :
    • Muscarinic acetylcholine receptor mAChRs
    • Adrenergic receptors
    • Adrenoreceptors
    • Dopamine receptors
    • 5-HT receptors (serotonin)
    • Opiate receptors
    • Receptors for peptides
    • Purine receptors
    • Chemokine receptors (e.g. olfactory and pheromone detection)
  • There are many subtypes
  • Many neurotransmitters can interact with both GPCRs and ligand-gated channels, allowing the same molecule to produce a wide variety of effects
  • However, individual peptide hormones generally act either on GPCRs or on kinase-linked receptors, but rarely on both. (Similarly applies to ligands that act on nuclear receptors)
  • Commonest single class of targets for therapeutic drugs
  • Molecular structure
    • A single polypeptide chain of up to 1100 residues
    • Seven transmembrane alpha-helices
    • An extracellular N-terminal domain
    • An intracellular C-terminal domain
    • Three different families (A, B and C)
      • The members of each individual family have considerable sequence homology, but there is none between the members of different families
      • All have the same heptahelical structure
      • Differ in:
        • The length of the extracellular N terminus
        • Location of the agonist binding domain
    • The long third cytoplasmic loop is the region of the molecule that couples the G-protein
    • Usually, a particular receptor subtype couples selectively with a particular G-protein, and swapping parts of the cytoplasmic loop between different receptors alters there G-protein selectivity
    • For small molecules (e.g. noradrenaline) the ligand-binding domain is buried in the cleft between the alpha-helical segments within the membrane (like slot occupied by retinal in the rhodopsin molecule
    • Peptide ligands (e.g. substance P) bind more superficially to the extracellular loops

Alternative mechanisms of receptor activation

  • Rhodopsin is a protein responsible for transduction in retinal rods. It is abundant in the retina and has the same structure as that in the diagram below.
    • It produces a response in the rod (hyperpolarisation, associated with inhibition of Na+ conductance) through a mechanism involving a G-protein
    • However, a photon (rather than an agonist molecule) produces the response
    • Rhodopsin incorporates its own inbuilt agonist molecule (“retinal”) which isomerises from the trans (inactive) to the cis (active) form when it absorbs a photon
  • Protease-activated receptors (PARs): Many proteases (e.g. thrombin – involved in blood clotting) activate PARs by snipping off the end of the extracellular N-terminal tail of the receptor. The expose N-terminal residues then bind to receptor domains in the extracellular loops, functioning as a “tethered agonist”
    • The receptor can be activated only once (cleavage cannot be reversed), so continuous resynthesis of receptor protein is necessary
    • Inactivation occurs by desensitisation, involving phosphorylation after which the receptor is internalised and degraded, to be replaced by newly synthesised protein

Alternate methods of activation

G-proteins and their role

  • Membrane-resident proteins
  • Function to recognise activated GPCRs and pass on the message to the effector systems that generate a cellular response
  • Middle man between receptors and the effector enzymes or ion channels
  • Called G-proteins because of their interaction with the guanine nucleotides GTP and GDP
  • Consist of three subunits: alpha, beta and gamma
    • Guanine nucleotides bind to the alpha subunit, which has enzymic activity, catalysing the conversion of GTP to GDP
    • The beta and gamma units remain together as a beta-gamma complex
    • All three subunits are anchored to the membrane through a fatty acid chain, coupled to the G-protein by a prenylation reaction
    • G-proteins are freely diffusible in the plane of a membrane, so a single pool of G-protein in a cell can interact with several different receptors and effectors
    • In their “resting” state, G-proteins are an alpha-beta-gamma trimer, with GDP occupying the site on the alpha subunit
    • When a GPCR is activated (by an agonist molecule), its conformation changes so that the cytoplasmic domain of the receptor acquires a high affinity for alpha-beta-gamma
    • Alpha-beta-gamma binds to the receptor causing the bound GDP to dissociate and be replaced with GTP (GDP-GTP exchange). Then the G-protein trimer dissociates, giving alpha-GTP and beta-gamma subunits (the “active” forms of the G-protein)
    • These active forms can diffuse into the membrane and associated with enzymes and ion channels, activating their targets
    • Signalling is terminated when the hydrolysis of GTP to GDP occurs through the GTPase activity of the alpha subunit. The alpha-GDP thus produced dissociated from the effector and reunites with beta-gamma
    • The effector regulates the GTPase activity of the alpha subunit (that is bound to the receptor), so that the activation of the effector is self-limiting
    • Amplification: a single agonist-receptor complex can activate several G-protein molecules, and each of these can remain associated with the effector enzyme for long enough to produce many molecules of product. The product is often a second messenger, and further amplification occurs before the final cellular response is produced
    • The pool of G-proteins in each cell has molecular variation in the alpha-subunits, allowing them to have different downstream effects

Targets for G-proteins

  • The main targets for G-proteins are:
    • Adenylyl cyclase, the enzyme responsible for cAMP formation
    • Phospholipase C, the enzyme responsible for inositol phosphate and diacylglycerol (DAG) formation
    • Ion channels, particularly Ca2+ and K+ channels
    • Rho A/Rho kinase, a system that controls the activity of many signalling pathways controlling cell growth and proliferation, smooth muscle contraction, etc

The adenylyl cyclase/cAMP system

  • cAMP is a nucleotide synthesised within the cell from ATP by the action of adenylyl cyclase (a membrane-bound enzyme)
    • Produced continuously
    • Inactivated by hydrolysis to 5’-AMP by phosphodiesterases (PDEs)
  • Many drugs, hormones and neurotransmitters act on GPCRs to increase or decrease the catalytic activity of adenylyl cyclase, changing the concentration of cAMP in the cell
  • cAMP regulates enzymes involved in:
    • Energy metabolism
    • Cell division
    • Cell differentiation
    • Ion transport
    • Ion channels
    • Contractile proteins in smooth muscle
  • All of these regulatory mechanisms occur through the activation of protein kinases by cAMP
  • Protein kinases control protein phosphorylation, which affects protein function
  • See the diagram below to see how cAMP is involved in controlling which stored energy (glycogen and fat) is made available as glucose to fuel muscle contraction
  • cAMP regulation via protein kinases also controls activity of voltage-activated calcium channels in heart muscle cells. Phosphorylation of these channels increases the amount of Ca2+ entering the cell during the action potential, and so increases the force of contraction of the heart
  • Receptors linked to G_i rather than G_s inhibit adenylyl cyclase, and thus reduce cAMP formation
  • cAMP is hydrolysed by phosphodiesterases (PDEs)

The phospholipase C/inositol phosphate system Inositol phosphates and intracellular calcium

  • Inositol (1,4,5) triophosphate is a water-soluble mediator that is released into the cytosol and acts on a specific receptor – the IP3 receptor – which is a ligand-gated calcium channel present on the membrane of the endoplasmic reticulum
  • IP3 controls the release of Ca2+ from intracellular stores
  • IP3 is converted inside the cell to IP4 by a kinase. IP4 is also involved in Ca2+ signalling

Diacylglycerol and protein kinase C

  • Diacylglycerol is produced as well as IP3 whenever receptor-induced PI hydrolysis occurs
  • DAG activatesprotein kinase C (PKC – a membrane-bound protein kinase), which catalyses the phosphorylation of intracellular proteins
  • DAG remains in the membrane and binds to a specific site on the PKC molecule, which migrates from the cytosol to the cell membrane and becomes activated by DAG.
  • PKCs are activated by DAG and increased intracellular Ca2+, both of which are produced by activation of GPCRs.
  • Some are also activated by arachidonic acid (generated by the action of phospholipases on membrane phospholipids), so PKC can also be activated by agonists that activate phospholipases.
  • NB: Kinases in general play a central role in signal transduction, and control many different aspects of cell function – the DAG-PKC link allows GPCRs to mobilise kinases to control signal transduction

Ion channels as targets for G-proteins

  • GPCRs can control ion channel function directly (without involving second messagers such as cAMP or inisotiol phosphates)
  • Direct interaction of the beta-gamma subunit of G0 and the channel, without the involvement of second messagers
  • E.g. in cardiac muscles, mAChRs enhance K+ permeability (hyperpolarising the cells and inhibiting electrical activity)

The Rho/Rho kinase system

  • Activated by certain GPCRs (and also by non-GPCR mechanisms). Affects GPCRs coupled to G12/G13 proteins
  • The free G-protein alpha subunit interacts with a guanosine nucleotide exchange factor, facilitating GDP-GTP exchange at Rho (which is another GTPase)
  • Rho-GDP is activated when GDP-GTP exchange occurs.
  • Active Rho then activates Rho kinase
  • Rho kinase phosphorylates many substrate proteins and controls many cellular functions

G-protein targets

Desensitisation of GPCRs

Desensitisation of GPCR by phosphorylation
  • Involves two main processes:
    • Receptor phosphorylation
    • Receptor internalisation (endocytosis)
  • Certain residues in the GPCR sequence (serine and threonine – most abundant in the C-terminal cytoplasmic tail) can be phosphorylated by kinases such as protein kinase A (PKA), PKC and specific membrane-bound GPCR kinases (GRKs)
  • Phosphorylation leads to impaired coupling between the activated receptor and the G-protein, reducing the agonist effect.
  • Heterologous desensitisation: kinases such as PKA and PKC, which are activated by many GPCRs, are not very selective. Thus receptors other than that for the desensitising agonist will also be affected. This sort of desensitisation is weak and short-lasting.
  • Homologous desensitisation: Phosphorylation by GRKs is receptor-specific and affects mainly receptors in their activated state. GRKs phosphorylate different residues from those targeted by other kinases, making them a binding site for arrestins.
  • Arrestins block the interaction with G-proteins and target the receptors for endocytosis, producing profound and long-lasting desensitisation.

Type 3: Kinase-linked and related receptors

  • This is a large and heterogeneous group of membrane receptors responding mainly to protein mediators
  • Have an extracellular ligand-binding domain linked to an intracellular domain by a single transmembrane helix.
  • The intracellular domain is enzymic (catalytic)
  • E.g. receptors for insulin, some cytokines and growth factors
  • Involved in effects that are exerted mainly at the level of gene transcription (cell division, growth, differentiation, inflammation, tissue repair, apoptosis and immune responses)
  • Most of these receptors are very large proteins with a single membrane-spanning helical region associated with a large extracellular ligand-binding domain and an intracellular domain of variable size and function
  • The main types are:
    • Receptor tyrosine kinases (RTKs)
    • Serine/threonin kinases
    • Cytokine receptors
    • Guanylyl cyclase-linked receptors

Protein phosphorylation and kinase cascade mechanisms

  • Protein phosphorylation is a key mechanism for controlling the function of proteins involved in regulating cellular processes
  • Kinases --> phosphorylation
  • Phosphatases --> dephosphorylation
  • Ligand binding to the receptor leads to dimerisation. The association of the two intracellular kinase domains allows mutual autophosphorylation of intracellular tyrosin residues
  • The phosphorylated tyrosine residues are then high-affinity docking sites for other intracellular proteins that form the next stage in the signal transduction cascade
  • Examples of such proteins include the SH2 domain proteins that recognise phosphotyrosine residues on the receptor.
  • Individual SH2 domain proteins bind selectively to particular receptors, so the events triggered by particular growth factors is highly specific
  • The end result is to activate or inhibit, by phosphorylation, a variety of transcription factors that migrate to the nucleus and suppress or induce the expression of particular genes

Examples of kinase-linked signal transduction pathways

  1. Ras/Raf pathway
    • Mediates the effect of growth factors and mitogens
    • Ras functions like a G-protein and convets the signal (by GDP/GTP exchange) from the SH2 domain protein Grb, which is phosphorylated by RTK
    • Active Ras then activates Raf, which is the first of a sequence of three serine/threonine kinases, each of which phosphorylates and activates the next in line
    • The last of these kinases is mitogen-activated protein (MAP) kinase. MAP kinases phosphorylates transcription factors that initiate gene expression, resulting cellular responses (e.g. cell division)
  2. Jak/Stat pathway (above diagram)
    • Involved in responses to many cytokines
    • Cytokine binds, causing dimerisation of the receptors
    • This attracts Jak (a cytosolic tyrosine kinase unit) to phosphorylate the receptor dimmer
    • Some Jaks have Stats (a family of transcription factors) as their targets.
    • Stats are SH2 domain proteins that bind to the phosphotyrosine groups on the receptor-Jak complex and are phosphorylated and activated.
    • Active Stat migrates to the nucleus and activates gene expression

Type 4: Nuclear receptors

  • Receptors that regulate gene transciption
  • Some are in the cytosol but migrate to the nucleus when a ligand is present
  • Include receptors for steroid hormones (e.g. oestrogen and gluccocorticoids), thyroid hormone and other agents such as retinoic acid and vitamin D. Important in endocrine signalling and metabolic regulation
  • Nuclear receptors are ligand-activated transcription factors that transduce signals by modifying gene expression
  • Not embedded in membranes, but are present in the soluble phase of the cell
  • Different behaviours once activated:
    • Some (such as steroid receptors) become mobile in the presence of their ligand and can translocate from the cytoplasm to the nucleus
    • Others such as the RXR remain in the nuclear compartment
  • Many act as lipid sensors and regulate lipid metabolism within the cell (link between our dietary and metabolic status and the expression of genes that regulate the metabolism and deposition of lipids)
  • Structure of nuclear receptors
    • Four modules
    • N-terminal domain
      • Most heterogeneous
      • Has the AF1 site that binds to other cell-specific transcription factors (ligand-independent) and modifies the binding or activity of the receptor
    • Core domain
      • Highly conserved
      • Structure responsible for DNA recognition and binding
      • Contains two zinc fingers: cysteine-rich loops in the amino acid chain that are held in a particular conformation by zinc ions. They recognise and bind the hormone response elements located in genes that are sensitive to regulation by this family of receptors
    • Hinge region
      • Highly flexible
      • Allows it to dimerise with other nuclear receptors and to exhibit DNA binding in a variety of configurations
    • C-terminal domain
      • Ligand-binding module and is specific to each class of receptor
      • AF2 region: is highly-conserved and is important in ligand-dependent activation

Classification of nuclear receptors

  • The nuclear receptor superfamily contains
    • Two main classes
    • A third class that shares some characteristics of both main classes
Class 1 receptors
  • Mainly receptors for steroid hormones
  • Examples:
    • Glucocorticoid and mineralocorticoid, oestrogen, progesterone, androgen receptors – GR, MR, ER, PR and AR respectively
  • Usually in the cytoplasm unless activated.
  • When inactive, they are complexed with heat shock and other proteins. May be reversibly attached to the cytoskeleton or other structures
  • Activation:
    • Diffusion/transportation of their ligand into the cell results in high-affinity binding between ligand and receptor
    • Receptors form homodimers and translocate to the nucleus, where they can transactivate or transrepress genes by binding to “positive” or “negative” hormone response elements
    • Large numbers of genes can be regulated by a single ligand
  • Usually recognise hormones that act in a negative feedback fashion to control biological events
Class 2 receptors
  • Ligands are lipids already present (to some extent) in the cell
  • Examples:
    • Peroxisome proliferator-activated receptor (PPAR) that recognises fatty acids
    • Liver oxysterol receptor (LXR) that recognises and acts as a cholesterol sensor
    • Farnesoid (bile acid) receptor (FXR)
    • Xenobiotic receptor (SXR) that recognises many foreign substances
    • Constitutive androstance receptor (CAR) which recognises androstane (a steroid) and some drugs
  • Act as heterodimers together with the retinoid receptor (RXR)
  • Mediate positive feedback effects (amplifies rather than inhibiting)
  • May form one of 2 types of heterodimer:
    • Non-permissive heterodimer (which can only be activated by the RXR ligand itself)
    • Permissive heterodimer (which can be activated either by retinoic acid or by its partner’s ligand)
Class 3 receptors (Hybrid class)
  • A subgroup of class 2 – they form heterodimers with RXR
  • HOWEVER, they don’t bind lipid ligands – instead they are involved in endocrine signalling
  • Examples:
    • Thyroid hormone receptor (TR)
    • Vitamin D receptor (VDR)
    • Retinoic acid receptor (RAR)

Control of gene transcription

  • Hormone response elements are 4-5 bp sequences of DNA to which nuclear receptors bind to modify gene transcription
    • Present symmetrically in pairs or half sites, although these may be arranged together in different ways
  • Ligand-bound receptor recruits further proteins including coactivators or corepressors to modify gene expression through its AF1 and AF2 domains
  • Some of these coactivators are enzymes involved in chromatin remodelling (e.g. histone acetylase – which regulates the unravelling of DNA to facilitate access by polymerase enzymes and hence gene transcription).
  • Corepressor complexes are recruited by some receptors and comprise histone acetylase and other factors that cause chromatin to become tightly packed (preventing further transcriptional activation)

Summary

Type 1: ligand-gated ion channels Type 2: G-protein-coupled receptors Type 3: receptor kinases Type 4: nuclear receptors'
Location Membrane Membrane Membrane Intracellular
Effector Ion channel Channel or enzyme Protein kinases Gene transcription
Coupling Direct G-protein Direct Via DNA
Examples Nicotinic acetylcholine receptor, GABA A receptor Muscarinic acetylcholine receptor, adrenoceptors Insulin, growth factors, cytokine receptors Steroid receptors
Structure Oligomeric assembly of subunits surrounding central pore Monomeric dimericor structure comprising seven transmembrane helices Single transmembrane helix linking extracellular receptor domain to intracellular kinase domain Monomeric structure with separate receptor- and DNA-binding domains

NB (GPCR):

  • Individual receptors show considerable sequence variation in particular regions, and the lengths of the main intracellular and extracellular domains also vary from one to another within the same family
  • However, the overall structural patterns and associated signal transduction pathways are very consistent