Allosteric modulator

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In biochemistry and pharmacology, an allosteric modulator is a substance that has the effects of an orthosteric ligand , e.g. B. an agonist or an inverse agonist , changed (modulated) a target protein, usually a receptor. Allosteric modulators bind to a different (allosteric) binding site than the orthosteric agonist binding site. They lead to a change in the conformation of the receptor protein , which changes the receptor affinity or the activity of the orthosteric ligand. The positive allosteric modulator (PAM) leads to an amplification, the negative allosteric modulator (NAM) to a weakening of the effects of an agonist or inverse agonist without itself, i.e. H. in the absence of an agonist or inverse agonist to show an effect. Substances that occupy the allosteric binding site, but are functionally neutral, are called silent modulators (SAM). Benzodiazepines have long been known drugs that act as allosteric modulators at GABA A receptors by increasing the activity of the transmitter GABA . Crystal structures of G-protein-coupled receptors , which were complexed with allosteric ligands , have been known since 2016 .

The natural environment of proteins can also affect their function. In this sense, lipids can have an allosterically modulating effect. This is important with regard to the nature of receptor- containing lipid membranes .

A distinction must be made between the modulators and allosteric agonists , which are able, in the absence of an orthosteric ligand, to activate a receptor directly by binding to an allosteric binding site. There are also ago-allosteric modulators that act both as allosteric agonists (activators) and as allosteric modulators.

In the English-language literature, the terms on-target and off-target allosterism are used to classify the location of binding and indicate whether a modulator binds to the same protein as the orthosteric ligand or whether it binds to a partner protein, as in GPCR - oligomers occurs.

literature

  • Christopoulos A, Kenakin T: G protein-coupled receptor allosterism and complexing . In: Pharmacol. Rev. . 54, No. 2, June 2002, pp. 323-74. PMID 12037145 .
  • Schwartz TW, Holst B: Allosteric enhancers, allosteric agonists and ago-allosteric modulators: where do they bind and how do they act? . In: Trends Pharmacol. Sci. . 28, No. 8, 2007, pp. 366-373. doi : 10.1016 / j.tips.2007.06.008 . PMID 17629958 .
  • Wenthur CJ, Gentry PR, Mathews TP, Lindsley CW: Drugs for Allosteric Sites on Receptors . In: Annu. Rev. Pharmacol. Toxicol. . 2013. doi : 10.1146 / annurev-pharmtox-010611-134525 . PMID 24111540 .

Individual evidence

  1. Zheng Y, Qin L, Zacarías NV, de Vries H, Han GW, Gustavsson M, Dabros M, Zhao C, Cherney RJ, Carter P, Stamos D, Abagyan R, Cherezov V, Stevens RC, IJzerman AP, Heitman LH, Tebben A, Kufareva I, Handel TM: Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists . In: Nature . 540, No. 7633, 2016, pp. 458-461. doi : 10.1038 / nature20605 . PMID 27926736 . PMC 5159191 (free full text).
  2. Oswald C, Rappas M, Kean J, Doré AS, Errey JC, Bennett K, Deflorian F, Christopher JA, Jazayeri A, Mason JS, Congreve M, Cooke RM, Marshall FH: Intracellular allosteric antagonism of the CCR9 receptor . In: Nature . 540, No. 7633, 2016, pp. 462-465. doi : 10.1038 / nature20606 . PMID 27926729 .
  3. Jazayeri A, Doré AS, Lamb D, Krishnamurthy H, Southall SM, Baig AH, Bortolato A, Koglin M, Robertson NJ, Errey JC, Andrews SP, Teobald I, Brown AJ, Cooke RM, Weir M, Marshall FH: Extra -helical binding site of a glucagon receptor antagonist . In: Nature . 533, No. 7602, 2016, pp. 274-7. doi : 10.1038 / nature17414 . PMID 27111510 .
  4. Liu X, Ahn S, Kahsai AW, Meng KC, Latorraca NR, Pani B, Venkatakrishnan AJ, Masoudi A, Weis WI, Dror RO, Chen X, Lefkowitz RJ, Kobilka BK: Mechanism of intracellular allosteric β2AR antagonist revealed by X- ray crystal structure . In: Nature . 548, No. 7668, 2017, pp. 480-484. doi : 10.1038 / nature23652 . PMID 28813418 .
  5. Dawaliby R, Trubbia C, Delporte C, Masureel M, Van Antwerpen P, Kobilka BK, Govaerts C: Allosteric regulation of G protein-coupled receptor activity by phospholipids . In: Nat Chem Biol . 12, No. 1, 2016, pp. 35-39. doi : 10.1038 / nchembio.1960 .