Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

Ao, Shpakov

doi:10.20944/preprints202302.0009.v1

Cited by 3 publications

(2 citation statements)

References 415 publications

(640 reference statements)

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“…Finally, the different functional effects displayed by 2,6-diazaspiro [3.4]octane and tryptoline acrylamide ligands targeting N112C-CCNE1 -inhibition of CDK2 and stabilization of CKS1B/CKS2 interactions, respectively -underscore the potential for allosteric sites to modulate distinct biochemical activities of proteins [67][68][69] . While we do not yet understand how promoting interactions with CKS1B/CKS2 may impact the function of CCNE1:CDK2 complexes, it is possible that tryptoline acrylamides displaying this property may function as substrateselective agonists in cells 45,46 .…”

Section: Discussionmentioning

confidence: 99%

Expanding the ligandable proteome by paralog hopping with covalent probes

Zhang,

Liu,

Hirschi

et al. 2024

Preprint

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More than half of the ~20,000 protein-encoding human genes have at least one paralog. Chemical proteomics has uncovered many electrophile-sensitive cysteines that are exclusive to a subset of paralogous proteins. Here, we explore whether such covalent compound-cysteine interactions can be used to discover ligandable pockets in paralogs that lack the cysteine. Leveraging the covalent ligandability of C109 in the cyclin CCNE2, we mutated the corresponding residue in paralog CCNE1 to cysteine (N112C) and found through activity-based protein profiling (ABPP) that this mutant reacts stereoselectively and site-specifically with tryptoline acrylamides. We then converted the tryptoline acrylamide-N112C-CCNE1 interaction into a NanoBRET-ABPP assay capable of identifying compounds that reversibly inhibit both N112C- and WT-CCNE1:CDK2 complexes. X-ray crystallography revealed a cryptic allosteric pocket at the CCNE1:CDK2 interface adjacent to N112 that binds the reversible inhibitors. Our findings thus provide a roadmap for leveraging electrophile-cysteine interactions to extend the ligandability of the proteome beyond covalent chemistry.

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Section: Discussionmentioning

confidence: 99%

Expanding the ligandable proteome by paralog hopping with covalent probes

Zhang,

Liu,

Hirschi

et al. 2024

Preprint

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“…By binding to the intracellular domain of PAR2, P2pal-18S is positioned to interfere with coupling to intracellular G proteins and subsequent signaling (Shpakov, 2023). For example, P2pal-18S reduces the stability of the Bcl-2 homolog Bcl-xL in colorectal carcinoma cells (Li et al, 2021), ERK and STAT3 signaling in cholangiocarcinoma cells (Kaufmann et al, 2012), and Bim expression as well as ERK signaling in murine neuronal cultures (Yoon et al, 2013).…”

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confidence: 99%

PARting Neuroinflammation with Protease-Activated Receptor 2 Pepducins

Scarisbrick

2024

J Pharmacol Exp Ther

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Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that results in demyelinating lesions and accumulating neurologic disability. Although the etiology of MS is incompletely understood, both genetic and environmental factors are implicated. The disease is characterized by T and B cells autoreactive to myelin-related epitopes that enter the CNS and orchestrate immune attacks. This results in injury to the oligodendrocytes, their myelin sheaths, and ultimately the axons they insulate (Baskaran et al., 2023). MS most commonly presents as a relapsing-remitting disease characterized by recurring inflammatory activity followed by full or partial recovery. Remission occurs in part by a process of remyelination that enhances nerve impulse conduction and provides axons with vital metabolic support (Nave and Werner, 2021). When neurologic disability progressively worsens and accumulates, the disease is termed secondary progressive MS. In a minority of cases, progressive disease is apparent from the outset and is termed primary progressive MS. The permanent disability that characterizes progressive stages reflects damage to axons and a microenvironment inhibitory to myelin regeneration (Absinta et al., 2020). Currently, there are 24 disease-modifying therapies available for MS (Baskaran et al., 2023). Notably, many of these have high efficacy for relapsing-remitting disease but show limited to no efficacy for progressive stages. Altogether, these data emphasize the complex pathogenesis of MS and that consideration of immune, neuronal, and glial mechanisms will be important in the design of therapies needed to halt disease and promote regenerative repair.

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Comparison of Steroidogenic and Ovulation-Inducing Effects of Orthosteric and Allosteric Agonists of Luteinizing Hormone/Chorionic Gonadotropin Receptor in Immature Female Rats

Derkach,

Lebedev,

Morina

et al. 2023

IJMS

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Gonadotropins, including human chorionic gonadotropin (hCG), are used to induce ovulation, but they have a number of side effects, including ovarian hyperstimulation syndrome (OHSS). A possible alternative is allosteric luteinizing hormone (LH)/hCG receptor agonists, including the compound TP4/2 we developed, which remains active when administered orally. The aim was to study the effectiveness of TP4/2 (orally, 40 mg/kg) as an ovulation inducer in FSH-stimulated immature female rats, compared with hCG (s.c., 15 IU/rat). TP4/2 stimulated progesterone production and corpus luteum formation; time-dependently increased the ovarian expression of steroidogenic genes (Star, Cyp11a1, Cyp17a1) and genes involved in ovulation regulation (Adamts-1, Cox-2, Egr-1, Mt-1); and increased the content of metalloproteinase ADAMTS-1 in the ovaries. These effects were similar to those of hCG, although in some cases they were less pronounced. TP4/2, in contrast to hCG, maintained normal LH levels and increased the ovarian expression of the LH/hCG receptor gene, indicating preservation of ovarian sensitivity to LH, and did not cause a sustained increase in expression of vascular endothelial growth factor-A involved in OHSS. Thus, TP4/2 is an effective ovulation inducer that, unlike hCG, has a lower risk of OHSS and ovarian LH resistance due to its moderate stimulating effect on steroidogenesis.

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Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

Cited by 3 publications

References 415 publications

Expanding the ligandable proteome by paralog hopping with covalent probes

Expanding the ligandable proteome by paralog hopping with covalent probes

PARting Neuroinflammation with Protease-Activated Receptor 2 Pepducins

Comparison of Steroidogenic and Ovulation-Inducing Effects of Orthosteric and Allosteric Agonists of Luteinizing Hormone/Chorionic Gonadotropin Receptor in Immature Female Rats

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