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In biochemistry, allosteric regulation is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site.
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agonist, while an inverse agonist causes an action opposite to that of the agonist.
A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of receptor proteins. They are sometimes called blockers; examples include alpha blockers, beta blockers, and calcium channel blockers. In pharmacology, antagonists have affinity but no efficacy for their cognate receptors, and binding will disrupt the interaction and inhibit the function of an agonist or inverse agonist at receptors. Antagonists mediate their effects by binding to the active site or to the allosteric site on a receptor, or they may interact at unique binding sites not normally involved in the biological regulation of the receptor's activity. Antagonist activity may be reversible or irreversible depending on the longevity of the antagonist–receptor complex, which, in turn, depends on the nature of antagonist–receptor binding. The majority of drug antagonists achieve their potency by competing with endogenous ligands or substrates at structurally defined binding sites on receptors.
Functional selectivity is the ligand-dependent selectivity for certain signal transduction pathways relative to a reference ligand at the same receptor. Functional selectivity can be present when a receptor has several possible signal transduction pathways. To which degree each pathway is activated thus depends on which ligand binds to the receptor. Functional selectivity, or biased signaling, is most extensively characterized at G protein coupled receptors (GPCRs). A number of biased agonists, such as those at muscarinic M2 receptors tested as analgesics or antiproliferative drugs, or those at opioid receptors that mediate pain, show potential at various receptor families to increase beneficial properties while reducing side effects. For example, pre-clinical studies with G protein biased agonists at the μ-opioid receptor show equivalent efficacy for treating pain with reduced risk for addictive potential and respiratory depression. Studies within the chemokine receptor system also suggest that GPCR biased agonism is physiologically relevant. For example, a beta-arrestin biased agonist of the chemokine receptor CXCR3 induced greater chemotaxis of T cells relative to a G protein biased agonist.
The beta-2 adrenergic receptor, also known as ADRB2, is a cell membrane-spanning beta-adrenergic receptor that binds epinephrine (adrenaline), a hormone and neurotransmitter whose signaling, via adenylate cyclase stimulation through trimeric Gs proteins, increases cAMP, and, via downstream L-type calcium channel interaction, mediates physiologic responses such as smooth muscle relaxation and bronchodilation.
The calcitonin receptor (CT) is a G protein-coupled receptor that binds the peptide hormone calcitonin and is involved in maintenance of calcium homeostasis, particularly with respect to bone formation and metabolism.
The glucagon-like peptide-1 receptor (GLP1R) is a G protein-coupled receptor (GPCR) found on beta cells of the pancreas and on neurons of the brain. It is involved in the control of blood sugar level by enhancing insulin secretion. In humans it is synthesised by the gene GLP1R, which is present on chromosome 6. It is a member of the glucagon receptor family of GPCRs. GLP1R is composed of two domains, one extracellular (ECD) that binds the C-terminal helix of GLP-1, and one transmembrane (TMD) domain that binds the N-terminal region of GLP-1. In the TMD domain there is a fulcrum of polar residues that regulates the biased signaling of the receptor while the transmembrane helical boundaries and extracellular surface are a trigger for biased agonism.
The human muscarinic acetylcholine receptor M5, encoded by the CHRM5 gene, is a member of the G protein-coupled receptor superfamily of integral membrane proteins. It is coupled to Gq protein. Binding of the endogenous ligand acetylcholine to the M5 receptor triggers a number of cellular responses such as adenylate cyclase inhibition, phosphoinositide degradation, and potassium channel modulation. Muscarinic receptors mediate many of the effects of acetylcholine in the central and peripheral nervous system. The clinical implications of this receptor have not been fully explored; however, stimulation of this receptor is known to effectively decrease cyclic AMP levels and downregulate the activity of protein kinase A (PKA).
Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the DRD2 gene. After work from Paul Greengard's lab had suggested that dopamine receptors were the site of action of antipsychotic drugs, several groups, including those of Solomon Snyder and Philip Seeman used a radiolabeled antipsychotic drug to identify what is now known as the dopamine D2 receptor. The dopamine D2 receptor is the main receptor for most antipsychotic drugs. The structure of DRD2 in complex with the atypical antipsychotic risperidone has been determined.
The muscarinic acetylcholine receptor M1, also known as the cholinergic receptor, muscarinic 1, is a muscarinic receptor that in humans is encoded by the CHRM1 gene. It is localized to 11q13.
The muscarinic acetylcholine receptor M2, also known as the cholinergic receptor, muscarinic 2, is a muscarinic acetylcholine receptor that in humans is encoded by the CHRM2 gene. Multiple alternatively spliced transcript variants have been described for this gene. It is Gi-coupled, reducing intracellular levels of cAMP.
The muscarinic acetylcholine receptor, also known as cholinergic/acetylcholine receptor M3, or the muscarinic 3, is a muscarinic acetylcholine receptor encoded by the human gene CHRM3.
The muscarinic acetylcholine receptor M4, also known as the cholinergic receptor, muscarinic 4 (CHRM4), is a protein that, in humans, is encoded by the CHRM4 gene.
Metabotropic glutamate receptor 2 (mGluR2) is a protein that, in humans, is encoded by the GRM2 gene. mGluR2 is a G protein-coupled receptor (GPCR) that couples with the Gi alpha subunit. The receptor functions as an autoreceptor for glutamate, that upon activation, inhibits the emptying of vesicular contents at the presynaptic terminal of glutamatergic neurons.
Metabotropic glutamate receptor 4 is a protein that in humans is encoded by the GRM4 gene.
Metabotropic glutamate receptor 5 is an excitatory Gq-coupled G protein-coupled receptor predominantly expressed on the postsynaptic sites of neurons. In humans, it is encoded by the GRM5 gene.
CDPPB is a drug used in scientific research which acts as a positive allosteric modulator selective for the metabotropic glutamate receptor subtype mGluR5. It has antipsychotic effects in animal models, and mGluR5 modulators are under investigation as potential drugs for the treatment of schizophrenia, as well as other applications.
AC-42 is a selective, allosteric agonist of the M1 muscarinic acetylcholine receptor. AC-42 was the first selective M1 agonist to be discovered and its derivatives have been used to study the binding domain of the M1 receptor.
Jan Steyaert is a Belgian bioengineer and molecular biologist. He started his career as an enzymologist but the Steyaertlab is best known for pioneering work on (engineered) nanobodies for applications in structural biology, omics and drug design. He is full professor and teaches biochemistry at the Vrije Universiteit Brussel and Director of the VIB-VUB Center for Structural Biology, one of the Research Centers of the Vlaams Instituut voor Biotechnologie (VIB). He was involved in the foundation of three spin-off companies: Ablynx, Biotalys, and Confo Therapeutics.
The amylin receptors (AMYRs) are heterodimers of the calcitonin receptor that are bound to by amylin with high affinity and consist of AMY1, AMY2, and AMY3. Amylin mimetics that are agonists at the amylin receptors are being developed as therapies for diabetes and obesity, and one, pramlintide, has been FDA approved. The AMY1 receptor may be activated by both amylin and the calcitonin gene-related peptide (CGRP) and could play a role in the effects of CGRP receptor antagonists developed for migraine. Dual agonists of the amylin and calcitonin receptors (DACRAs) are under development for obesity. Amylin and its receptors are believed to play a role in Alzheimer's disease.
References
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- ↑ "Professor Arthur Christopoulos named new Dean". Faculty of Pharmacy and Pharmaceutical Sciences. Retrieved 12 August 2019.
- ↑ "Neuromedicines Discovery Centre". Neuromedicines Discovery Centre. Retrieved 18 November 2021.
- ↑ "Twenty-two Australians recognised among our nation's most distinguished scientists | Australian Academy of Science". www.science.org.au. Retrieved 25 May 2021.
- ↑ "2013 Award Winners". American Society for Pharmacology and Experimental Therapeutics . Retrieved 1 February 2015.
- ↑ "WCP 2014: 17th World Congress of Basic and Clinical Pharmacology in Cape Town". guidetopharmacology blog. 24 March 2014. Retrieved 13 August 2019.
- ↑ Thomaidou, Zoe (28 October 2015). "Prof. Christopoulos receives honorary doctorate | Neos Kosmos". English Edition. Retrieved 13 August 2019.
- ↑ Gaddum Memorial Lecture 2016: Professor Arthur Christopoulos , retrieved 13 August 2019
- ↑ "Previous Winners | GSK Australia". au.gsk.com. Retrieved 13 August 2019.
- ↑ "Highly Cited Researchers - The Most Influential Scientific Minds". HCR. Archived from the original on 20 February 2019. Retrieved 13 August 2019.
- ↑ "Highly Cited Researchers". publons.com. Retrieved 18 November 2021.
- ↑ "Fellowship". AAHMS - Australian Academy of Health and Medical Sciences. Retrieved 13 August 2019.
- ↑ BPS, London (19 December 2018). "2018 Fellowships announced" . Retrieved 13 August 2019.
