Collateral efficacy in drug discovery: taking advantage of the good (allosteric) nature of 7TM receptors

Kenakin, Terry

doi:10.1016/j.tips.2007.06.009

Cited by 196 publications

(154 citation statements)

References 65 publications

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“…2E), our model identifies residues 113-115, 182-184, and 299-301 (located in the immediate environment of the retinal cofactor), residues 135-137, which nearly coincide with the ERY motif [residues 134-136 (40)], and residues 66-68, 225-227, 143-147, 235-245, and 312-323 (the eighth α-helix), which are also known to participate in G-protein binding (40). Our model also suggests that loop residues 278-283 at the periplasmic side may be involved in allosteric regulation by influencing ligand binding (47,48).…”

Section: Resultsmentioning

confidence: 55%

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Coarse-grained modeling of allosteric regulation in protein receptors

Balabin¹,

Yang²,

Beratan

2009

Proc. Natl. Acad. Sci. U.S.A.

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Allosteric regulation provides highly specific ligand recognition and signaling by transmembrane protein receptors. Unlike functions of protein molecular machines that rely on large-scale conformational transitions, signal transduction in receptors appears to be mediated by more subtle structural motions that are difficult to identify. We describe a theoretical model for allosteric regulation in receptors that addresses a fundamental riddle of signaling: What are the structural origins of the receptor agonism (specific signaling response to ligand binding)? The model suggests that different signaling pathways in bovine rhodopsin or human β 2 -adrenergic receptor can be mediated by specific structural motions in the receptors. We discuss implications for understanding the receptor agonism, particularly the recently observed "biased agonism" (selected activation of specific signaling pathways), and for developing rational structure-based drug-design strategies. allostery | signal transduction | agonism | GPCRA llostery [Greek for "other site" (1, 2)] indicates a mechanism in which a stimulus acting at a regulatory protein site (often called the orthosteric site or the effector site) causes a response at a spatially distant functional site (the allosteric site) (3). Allosteric regulatory mechanisms (i.e., regulation of protein functions by binding an effector molecule at an allosteric site) are ubiquitous throughout biology; they control vital biomolecular and cellular functions, including enzymatic catalysis and biosynthesis, molecular recognition and response to messengers, cell signaling, energy transduction, cell division and cancer, and many others (4-7). Signaling is perhaps the most fascinating and significant set of processes in which allosteric communication plays a central role (8, 9); biochemical signaling pathways lie at the core of most biological processes in cells, most notably signaling responses to binding endogenous ligands and drugs (10-12). Therefore, an understanding of allosteric signal transduction mechanisms in protein receptors is critical for describing cell regulation.The investigation of allosteric regulatory mechanisms in signaling is difficult because of the complexity of receptor structure, the presence of thermal fluctuations, the range of relevant time scales, and, often, the subtlety of the underlying structural changes (13-15). Although experimental techniques such as FRET (16), time-resolved X-ray crystallography (17), time-resolved spectroscopy (18), cryo-EM (19), and biochemical methods (20, 21) provide valuable insights into specific aspects of allosteric interactions, a comprehensive atomic-level description of the connection between receptor structure and signaling is still beyond reach. As such, advanced computational methods could be instrumental for revealing the structural origins of allosteric regulation in signal transduction.Computational approaches have been used recently in attempts to explore signal transduction in receptors. Although all-atom molecular dynamics (M...

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Section: Resultsmentioning

confidence: 55%

“…If the receptor mediates 2 or more signaling pathways, ligand binding could activate one pathway but suppress another. Indeed, selected activation of the "G protein-mediated" pathway or the "β-arrestin-mediated" pathway in B2AR (termed "biased agonism" or "functional selectivity") has been recently discovered in experiments (47,48).…”

Section: Discussionmentioning

confidence: 99%

Coarse-grained modeling of allosteric regulation in protein receptors

Balabin¹,

Yang²,

Beratan

2009

Proc. Natl. Acad. Sci. U.S.A.

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“…GPCR ligands that sequester their receptor generally have agonist activity, although exceptions have been noted (26), including CCR5 ligands (27,28). 5P14-RANTES now appears to be a robust example of a CCR5 ligand that does not activate G protein-linked signaling but induces intracellular sequestration (Table 1, Fig.…”

Section: Ref 16)mentioning

confidence: 99%

Highly potent, fully recombinant anti-HIV chemokines: Reengineering a low-cost microbicide

Gaertner

Cerini

Escola

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

129

223

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New prevention strategies for use in developing countries are urgently needed to curb the worldwide HIV/AIDS epidemic. The N-terminally modified chemokine PSC-RANTES is a highly potent entry inhibitor against R5-tropic HIV-1 strains, with an inhibitory mechanism involving long-term intracellular sequestration of the HIV coreceptor, CCR5. PSC-RANTES is fully protective when applied topically in a macaque model of vaginal HIV transmission, but it has 2 potential disadvantages related to further development: the requirement for chemical synthesis adds to production costs, and its strong CCR5 agonist activity might induce local inflammation. It would thus be preferable to find a recombinant analogue that retained the high potency of PSC-RANTES but lacked its agonist activity. Using a strategy based on phage display, we set out to discover PSC-RANTES analogs that contain only natural amino acids. We sought molecules that retain the potency and inhibitory mechanism of PSC-RANTES, while trying to reduce CCR5 signaling to as low a level as possible. We identified 3 analogues, all of which exhibit in vitro potency against HIV-1 comparable to that of PSC-RANTES. The first, 6P4-RANTES, resembles PSC-RANTES in that it is a strong agonist that induces prolonged intracellular sequestration of CCR5. The second, 5P12-RANTES, has no detectable G protein-linked signaling activity and does not bring about receptor sequestration. The third, 5P14-RANTES, induces significant levels of CCR5 internalization without detectable G protein-linked signaling activity. These 3 molecules represent promising candidates for further development as topical HIV prevention strategies.HIV/AIDS ͉ phage display ͉ CCR5 ͉ PSC-RANTES

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“…This characteristic feature of allosteric interactions is called 'probe dependence' (Kenakin, 2007;Leach et al, 2007) because the cooperativity between the two binding sites depends on the properties of the orthosteric ligand used as a probe of receptor binding or function. A striking example of this phenomenon is shown in Figure 1, in which it can be seen that LY2033298 minimally perturbed the binding of two structurally distinct orthosteric antagonists, Table 1).…”

Section: Ly2033298 Exhibits 'Probe Dependence' and Redistributes The mentioning

confidence: 99%

Molecular Mechanisms of Action and In Vivo Validation of an M4 Muscarinic Acetylcholine Receptor Allosteric Modulator with Potential Antipsychotic Properties

Leach

Loiacono

Felder

et al. 2009

Neuropsychopharmacol

149

169

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We recently identified LY2033298 as a novel allosteric potentiator of acetylcholine (ACh) at the M 4 muscarinic acetylcholine receptor (mAChR). This study characterized the molecular mode of action of this modulator in both recombinant and native systems. Radioligandbinding studies revealed that LY2033298 displayed a preference for the active state of the M 4 mAChR, manifested as a potentiation in the binding affinity of ACh (but not antagonists) and an increase in the proportion of high-affinity agonist-receptor complexes. This property accounted for the robust allosteric agonism displayed by the modulator in recombinant cells in assays of [ 35 S]GTPgS binding, extracellular regulated kinase 1/2 phosphorylation, glycogen synthase kinase 3b phosphorylation, and receptor internalization. We also found that the extent of modulation by LY2033298 differed depending on the signaling pathway, indicating that LY2033298 engenders functional selectivity in the actions of ACh. This property was retained in NG108-15 cells, which natively express rodent M 4 mAChRs. Functional interaction studies between LY2033298 and various orthosteric and allosteric ligands revealed that its site of action overlaps with the allosteric site used by prototypical mAChR modulators. Importantly, LY2033298 reduced [ 3 H]ACh release from rat striatal slices, indicating retention of its ability to allosterically potentiate endogenous ACh in situ. Moreover, its ability to potentiate oxotremorine-mediated inhibition of condition avoidance responding in rodents was significantly attenuated in M 4 mAChR knockout mice, validating the M 4 mAChR as a key target of action of this novel allosteric ligand.

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Collateral efficacy in drug discovery: taking advantage of the good (allosteric) nature of 7TM receptors

Cited by 196 publications

References 65 publications

Coarse-grained modeling of allosteric regulation in protein receptors

Coarse-grained modeling of allosteric regulation in protein receptors

Highly potent, fully recombinant anti-HIV chemokines: Reengineering a low-cost microbicide

Molecular Mechanisms of Action and In Vivo Validation of an M4 Muscarinic Acetylcholine Receptor Allosteric Modulator with Potential Antipsychotic Properties

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