Discovery of a novel ligand that modulates the protein–protein interactions of the AAA+ superfamily oncoprotein reptin

Healy, Alan R.; Houston, Douglas R.; Remnant, Lucy; Huart, Anne-Sophie; Brychtová, Veronika; Maslon, Magdalena M.; Meers, Olivia; Müller, Petr; Krejčí, Adam; Blackburn, Elizabeth A.; Vojtesek, Borek; Hernychová, Lenka; Walkinshaw, Malcolm D.; Westwood, Nicholas J.; Hupp, Ted R.

doi:10.1039/c4sc03885a

Cited by 12 publications

(17 citation statements)

References 39 publications

(54 reference statements)

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“…On a local scale, protein-protein interfaces show dynamic patterns with distinct thermal fluctuations [42]; on a global scale, allosteric changes in structure may explain some of the entropic gain in binding [43]; a distant mutation that induces a large conformational change may disrupt the dimerization of an enzyme [44]; or, the functional effect of N -glycosylation is not through changes in protein structure but decreases in protein dynamics, and an increase in protein stability modulates the oligomerization and aggregation states of the glycosylated protein[45]. Likewise, a nucleotide-mimetic was shown to modulate the oligomerization state of the oncoprotein reptin by altering its global conformation and protein-binding activity [46•]. Finally, an approach based on the maximization of information entropy change associated with the global modes between bound and unbound structures significantly helps in distinguishing the native protein complex structures from the designed complex structures [47].…”

Section: Introductionmentioning

confidence: 99%

Adaptability of protein structures to enable functional interactions and evolutionary implications

Haliloğlu

Bahar

2015

Current Opinion in Structural Biology

110

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Several studies in recent years have drawn attention to the ability of proteins to adapt to intermolecular interactions by conformational changes along structure-encoded collective modes of motions. These so-called soft modes, primarily driven by entropic effects, facilitate, if not enable, functional interactions. They represent excursions on the conformational space along principal low-ascent directions/paths away from the original free energy minimum, and they are accessible to the protein even prior to protein-protein/ligand interactions. An emerging concept from these studies is the evolution of structures or modular domains to favor such modes of motion that will be recruited or integrated for enabling functional interactions. Structural dynamics, including the allosteric switches in conformation that are often stabilized upon formation of complexes and multimeric assemblies, emerge as key properties that are evolutionarily maintained to accomplish biological activities, consistent with the paradigm sequence → structure → dynamics → function where ‘dynamics’ bridges structure and function.

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Section: Introductionmentioning

confidence: 99%

Adaptability of protein structures to enable functional interactions and evolutionary implications

Haliloğlu

Bahar

2015

Current Opinion in Structural Biology

110

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“…In addition, small molecule drug leads have recently been identified that bind to Reptin and alter AGR2-Reptin complex stability [38] that might provide chemical biology tools for future research into the significance of AGR2 in the Reptin signalling pathway. The effects of monomer to dimer equilibrium on AGR2 oncogenic and inflammatory signalling is not defined presently, but presumably additional AGR2 client or regulatory proteins will exploit the monomer to dimer inter-conversion as a association-dissociation cycle in the AGR2 protein folding pathway (Fig.…”

Section: Agr2 Binding Proteinsmentioning

confidence: 99%

Mechanisms of anterior gradient-2 regulation and function in cancer

Brychtová

Mohtar

Vojtěšek

et al. 2015

Seminars in Cancer Biology

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“…Amidové vodíky vystavené na povrchu proteinu jsou vyměňovány za vodíky HDX-MS byla např. použita pro ověření interakce mezi navrženým nízkomolekulárním ligandem a onkoproteinem Reptin [30]. Analýza potvrdila protein--ligandovou interakci a navíc s přesností na peptidy určila interakční místo.…”

Section: Hdx-msunclassified

Utilization of Hydrogen/Deuterium Exchange in Biopharmaceutical Industry

Coufalová¹,

Vojtěšek²,

Hernychová³

2016

Klin Onkol

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Regionální centrum aplikované molekulární onkologie, Masarykův onkologický ústav, Brno Souhrn Východiska: Vývoj bio farmaceutik je nejrychleji se rozvíjející oblastí dnešního farmaceutického průmyslu. Analýza proteinových terapeutik je však velice náročný úkol kvůli jejich velikosti a komplexnosti prostorové struktury. Jakékoliv změny v primární, sekundární, terciální či kvarterní struktuře proteinů mohou mít výrazný vliv na jejich funkci, účinnost a v neposlední řadě i toxicitu. Hmotnostní spektrometrie se v minulosti osvědčila jako kvalitní nástroj pro analýzu primární struktury proteinů (aminokyselinové sekvence) a v posledních letech je díky rozvoji nových metod schopná analyzovat i vyšší proteinové struktury. Jednou z těchto nových metod je vodík/ deuteriová výměna (HDX). HDX je založena na výměně amidových vodíků aminokyselinového řetězce za deuteria z okolního roztoku. Vodíky nacházející se na povrchu proteinu jsou za deuteria vyměňovány mnohem rychleji než vodíky schované uvnitř proteinu. Získané výsledky z HDX metody mohou poskytnout informace o prostorové struktuře proteinu a také o protein-proteinových a protein-ligandových interakcí. Navíc analýzou výměny deuterií v různých časových intervalech může tato metoda poskytnout informace i o dynamických změnách proteinové struktury a dynamice proteinových interakcí. Vzhledem k možnostem, které tato metoda nabízí, se HDX stala atraktivní metodou pro charakterizaci proteinových bio farmaceutik. Cíl: Cílem tohoto přehledového článku je poukázat na možnosti využití hmotnostní spektrometrie v bio farmaceutickém průmyslu se zaměřením na metodu HDX a její aplikace. Klíčová slovahmotnostní spektrometrie -proteomika -konformace proteinů -objevování léků -farmaceutický průmysl -vodík/ deuteriová výměna Summary Background: The development of bio pharmaceutics is the fastest growing segment of the present pharmaceutical industry. The analysis of proteins therapeutics is a challenging task due to their large size and complexity of spatial structure. Any changes in the primary, secondary, tertiary or quaternary protein structure can have huge impact on their function, efficiency and toxicity. Mass spectrometry proved itself to be a powerful tool for analysis of primary protein structure (amino acid sequence) and thanks to the development of new techniques in last years it is able to analyse higher order protein structures. One of these new techniques is hydrogen/ deuterium exchange (HDX). HDX is based on exchange of amid protons with deuterium from solution on the protein backbone chain. Protons on the surface of protein are exchanging with deuterium much faster than protons buried inside of protein. HDX results could provide information about spatial protein structure and also about protein-protein interactions and protein-ligand interactions. Furthermore, by analysing of deuterium exchange in different time points this method could give information about dynamic changes of protein structure and dynamics of proteins interactions. Because of possibilities of this method,...

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Discovery of a novel ligand that modulates the protein–protein interactions of the AAA+ superfamily oncoprotein reptin

Abstract: Discovery and use of a chemical tool.

Cited by 12 publications

References 39 publications

Adaptability of protein structures to enable functional interactions and evolutionary implications

Adaptability of protein structures to enable functional interactions and evolutionary implications

Mechanisms of anterior gradient-2 regulation and function in cancer

Utilization of Hydrogen/Deuterium Exchange in Biopharmaceutical Industry

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