RECEPTOR – LIGAND INTERACTION

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BOTANY: SEM-VI, PAPER-C13T: PLANT METABOLISM, UNIT-8: Mechanisms of signal transduction.

RECEPTOR – LIGAND INTERACTION

A receptor–ligand complex is a complex of a receptor bound with a ligand that is formed following molecular recognition between receptor that interact with various other molecules(ligand). Formation of a receptor -ligand complex is based on molecular recognition between biological macromolecules and ligands, where ligand means any molecule that binds the receptor with high affinity and specificity.

INTERACTIONS

The receptor -ligand complex is a reversible non-covalent interaction between two biological (macro)molecules. In non-covalent interactions there is no sharing of electrons like in covalent interactions or bonds. Non-covalent binding may depend on hydrogen bonds, hydrophobic forces, van der Waals forces, π-π interactions, electrostatic interactions in which no electrons are shared between the two or more involved molecules.

The highest possible affinity from a receptor towards the ligand, or target molecule, can be observed when the protein has a perfect mirror image of the shape of the target surface together with a charge distribution that complements perfectly the target surface.

The affinity between receptor and ligand is given by the equilibrium dissociation constant Kd that relates the concentrations of the complexed and uncomplexed species in solution.

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FIG: Diagrammatic representation of a Receptor- ligand Interaction.

The dissociation constant is defined as

Kd = [L] [P]

[LP]

where [L], [P] and [LP] represent molar concentrations of the protein(Receptor), ligand and complex, respectively.

The lower the Kd value the higher the affinity of the protein for the ligand and vice versa.

Receptor –ligand complexes can be found in almost any cellular process. Binding of a ligand causes a conformational change in the protein and often also in the

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ligand. This change initiates a sequence of events leading to different cellular functions. The complexes are formed by different molecules like macromolecules as in protein complexes, protein DNA or protein RNA complexes as well as by proteins that bind smaller molecules like peptides, lipids, carbohydrates, small nucleic acids. They may have various functions within the cell: catalysis of chemical reactions (enzyme-substrate), defence of the organism through the immune system (complexes of antibodies antigen), signal transduction (receptor-ligand complexes) that consists of a transmembrane receptor that upon binding the ligand activates an intracellular cascade. Lipophilic hormonal receptor complexes can pass the nuclear membrane where transcription may be regulated.

SECONDARY MESSENGERS

Second messengers are intracellular signalling molecules released by the cell in response to exposure to extracellular signalling molecules—the first messengers. (Intracellular signals, a non-local form or cell signalling, encompassing both first messengers and second messengers, are classified as juxtracrine, paracrine, and endocrine depending on the range of the signal.) Second messengers trigger physiological changes at cellular level such as proliferation, migration, survival, apoptosis, differentiation and depolarisation. They are one of the triggers of intracellular signal transduction cascades. Examples of second messenger molecules include cyclic AMP, cyclic GMP, inositol triphosphate, diacylglycerol, and calcium. First

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messengers are extra-cellular factors, often hormones/neurotransmitters- such as epinephrine, growth hormone, and serotonin. Peptide hormones and neurotransmitters are hydrophilic molecules, these first messengers may not physically cross the phospholipid bilayer to initiate changes within the cell directly—unlike steroid hormones, which usually do. This functional limitation requires the cell to have signal transduction mechanisms to transduce first messenger into second messengers, so that the extracellular signal may be propagated intracellularly. An important feature of the second messenger signalling system is that second messengers may be coupled downstream to multi-cyclic kinase cascades to greatly amplify the strength of the original first messenger signal. For example, RasGTP signals link with the mitogen activated protein kinase (MAPK) cascade to amplify the allosteric activation of proliferative transcription factors such as Myc and CREB.

FIG: Diagrammatic representation of the secondary messenger concept.

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Types of secondary messengers

There are three basic types of secondary messenger molecules:

 Hydrophobic molecules: molecules that are water insoluble such as diacylglycerol, and phosphatidylinositols, which are membrane- associated and diffuse from the plasma membrane into the intermembrane space where they can reach and regulate membrane-associated effector proteins.

 Hydrophilic molecules: molecules that are water-soluble, such as cAMP, cGMP, IP3, and Ca²⁺, that are located within the cytosol.

 Gases: nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) which can diffuse both through cytosol and across cellular membranes.

These intracellular messengers have some properties in common:

 They can be synthesized/released and broken down again in specific reactions by enzymes or ion channels.

 Some (such as Ca²⁺) can be stored in special organelles and quickly released when needed.

 Their production/release and destruction can be localized, enabling the cell to limit space and time of signal activity.

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CALCIUM CALMODULIN

Ca²⁺ is a secondary messenger. They are intercellular within the cell which are activated by first messengers. First messengers are always extracellular in nature. These first messengers relay the signal and transmit the signal to the cell and initiate a pathway in which second messengers will induce a cellular response, causing it to open. Secondary messengers are therefore one of the initiating components of intracellular transduction cascade. Example of intracellular secondary messenger includes cyclic GMP, IP³, Ca²⁺. The Ca²⁺is the most common intracellular messenger in the neurons.

Pathway of the Ca²⁺ Secondary messenger

 The cell membrane has ligand gated Ca²⁺channel, where ligand binds to the Ca²⁺causing it to open and let Ca²⁺in to the cell.

 The cell also has voltage channel across the plasma membrane causing a voltage sensitive Ca²⁺channel to open. This transient rise increases the cytoplasmic Ca²⁺ concentration transmits information within the cell.

 The rise in Ca²⁺ allows a large number of Ca²⁺ to bind to the large number of Ca²⁺binding proteins that serve as molecular target such as calmodulin which is abundant in the cytosol of all cell. Binding of Ca²⁺ to this calmodulin activates this protein.

 Calmodulin then activates further signalling pathways by binding to downstream targets such as protein kinases.

Calmodulin is a ubiquitous regulatory protein of the second-messenger system. It exhibits Ca²⁺-dependent regulatory activities toward several

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enzymes and proteins. The protein is implicated in a variety of cellular processes that are established as Ca²⁺-modulated. These include cyclic nucleotide and Ca²⁺ metabolisms, muscle contraction, secretory processes, microtubule and mitotic apparatus assembly, and glycogen metabolism. Thus, calmodulin plays a central role in the second- messenger system as a general mediator of the Ca²⁺ signal.

Fig: Calcium calmodulin pathway

References:

https://en.wikipedia.org/wiki/Protein%E2%80%93ligand_complex https://en.wikipedia.org/wiki/Second_messenger_system