Identification of a Putative Sordarin Binding Site inCandida albicans Elongation Factor 2 by Photoaffinity Labeling

Domínguez, Juan M.; Martin, J.J.

doi:10.1074/jbc.m104183200

Cited by 9 publications

(9 citation statements)

References 32 publications

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“…Additionally, the group of sordarins has been enlarged by azasordarin derivatives, including sordarin oxime derivatives (Serrano- , sordarin morpholino derivatives (Serrano-Wu et al, 2003), N-substituted 1,4-oxazepanyl sordarins (Kaneko et al, 2002), oxazepine sordarins (Serrano- Wu, Laurent, Chen, et al, 2002), isoxazoline sordarins, isoxazole sordarins (Serrano- , FR29581 (Hanadate et al, 2009), and GM258383 (Dominguez & Martin, 2001). These derivatives were mainly centred on the glycoside part to improve the anti-fungal spectrum, cell uptake, and biological activity or to reduce toxicity.…”

Section: Chemical Structurementioning

confidence: 99%

Sordarin— An anti‐fungal antibiotic with a unique modus operandi

Shao

Molestak

et al. 2022

British J Pharmacology

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Fungal infections cause serious problems in many aspects of human life, in particular infections in immunocompromised patients present serious problems. Current antifungal antibiotics target various metabolic pathways, predominantly the cell wall or cellular membrane metabolism. Numerous compounds are available to combat fungal infections, but their efficacy is far from satisfactory and some of them display high toxicity. The emerging antibiotic resistance represents a serious issue as well. Hence, there is a considerable need for new anti-fungal compounds with lower toxicity and higher effectiveness. One of the unique anti-fungal antibiotics is sordarin, the only known compound that acts on the fungal translational machinery per se. Sordarin inhibits protein synthesis at the elongation step of the translational cycle, acting on eukaryotic translation elongation factor 2. In this review, we deliver a robust scientific platform promoting the development of anti-fungal compounds, in particular focusing on the molecular action of sordarin.

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Section: Chemical Structurementioning

confidence: 99%

Sordarin— An anti‐fungal antibiotic with a unique modus operandi

Shao

Molestak

et al. 2022

British J Pharmacology

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“…Sordarin inhibits translation by stabilizing the eEF2‐ribosome complex by directly binding to eEF2 [61] . Sordarin binds to the purified C. albicans eEF2 at a single binding site with a K d of 1.26 μM [62] . The presence of ribosomes dramatically enhances the affinity of sordarin for eEF2 ( K d = 0.7 nM) and also results in an additional binding site with a K d of 41.5 nM.…”

Section: Sordarinmentioning

confidence: 99%

“…using a photoreactive sordarin analog ([ 14 C]‐GM258383, Figure 5C). [62] The probe contains a photoactivatable arylazide group in place of the sugar moiety and inhibits protein synthesis at a concentration comparable to that of the parent natural product in the C. albicans cell‐free system. The specificity of photolabeling was verified by a competition experiment, in which an excess of sordarin prevented the photoreactive sordarin probe from labeling eEF2.…”

Section: Sordarinmentioning

confidence: 99%

Deciphering the Biological Activities of Antifungal Agents with Chemical Probes

Fridman

Sakurai

2023

Angew Chem Int Ed

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The growing number of fungal infections caused by pathogens resistant to one or more classes of antifungal drugs emphasizes the threat that these microorganisms pose to animal and human health and global food security. Open questions remain regarding the mechanisms of action of the limited repertoire of antifungal agents, making it challenging to rationally develop more efficacious therapeutics. In recent years, the use of chemical biology approaches has resolved some of these questions and has provided new promising concepts to guide the design of antifungal agents. By focusing on examples from studies carried out in recent years, this minireview describes the key roles that probes based on antifungal agents and their derivatives have played in uncovering details about their activities, in detecting resistance, and in characterizing the interactions between these agents and their targets.

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“…From genetic studies, three amino acids within residues 521±524 in yeast are vital for sordarin selectivity (Shastry et al, 2001) and the homologous region in EF-G is located in domain 3 of the protein. However, recent cross-linking experiments between a photoactivatable sordarin derivative and eEF2 map the binding site to the G HH subdomain of eEF2, far away from the selectivity region in domain 3 (Dominguez & Martin, 2001).…”

Section: Introductionmentioning

confidence: 99%

Purification and crystallization of the yeast elongation factor eEF2

Jørgensen

Carr-Schmid

Ortiz

et al. 2002

Acta Crystallogr D Biol Crystallogr

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Crystals of the Saccharomyces cerevisiae elongation factor 2 (eEF2) in complex with GDP were obtained with the vapour-diffusion technique after rapid puri®cation from industrial yeast. The crystals diffract to 2.85 A Ê and belong to the space group P2 1 2 1 2 1 . A yeast strain expressing a functional histidine-tagged eEF2 as the only form of the protein further allows facilitated puri®cation of the factor for both structural and functional studies.

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Identification of a Putative Sordarin Binding Site inCandida albicans Elongation Factor 2 by Photoaffinity Labeling

Cited by 9 publications

References 32 publications

Sordarin— An anti‐fungal antibiotic with a unique modus operandi

Sordarin— An anti‐fungal antibiotic with a unique modus operandi

Deciphering the Biological Activities of Antifungal Agents with Chemical Probes

Purification and crystallization of the yeast elongation factor eEF2

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