dc.contributor.author
Wong, Ee Lin
dc.contributor.author
Nawrotzky, Eric
dc.contributor.author
Arkona, Christoph
dc.contributor.author
Kim, Boo Geun
dc.contributor.author
Beligny, Samuel
dc.contributor.author
Wang, Xinning
dc.contributor.author
Wagner, Stefan
dc.contributor.author
Lisurek, Michael
dc.contributor.author
Carstanjen, Dirk
dc.contributor.author
Rademann, Jörg
dc.date.accessioned
2019-05-24T11:25:34Z
dc.date.available
2019-05-24T11:25:34Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/24647
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-2410
dc.description.abstract
Protein-templated fragment ligations have been established as a powerful method for the assembly and detection of optimized protein ligands. Initially developed for reversible ligations, the method has been expanded to irreversible reactions enabling the formation of super-additive fragment combinations. Here, protein-induced Mannich ligations are discovered as a biocatalytic reaction furnishing inhibitors of the transcription factor STAT5. STAT5 protein catalyzes multicomponent reactions of a phosphate mimetic, formaldehyde, and 1H-tetrazoles yielding protein ligands with greatly increased binding affinity and ligand efficiency. Reactions are induced under physiological conditions selectively by native STAT5 but not by other proteins. Formation of ligation products and (auto-)inhibition of the reaction are quantified and the mechanism is investigated. Inhibitors assembled by STAT5 block specifically the phosphorylation of this protein in a cellular model of acute myeloid leukemia (AML), DNA-binding of STAT5 dimers, expression of downstream targets of the transcription factor, and the proliferation of cancer cells in mice.
en
dc.rights.uri
https://creativecommons.org/licenses/by/4.0/
dc.subject
Biocatalysis
en
dc.subject
Drug discovery and development
en
dc.subject
Target validation
en
dc.subject.ddc
500 Naturwissenschaften und Mathematik::500 Naturwissenschaften::500 Naturwissenschaften und Mathematik
dc.title
The transcription factor STAT5 catalyzes Mannich ligation reactions yielding inhibitors of leukemic cell proliferation
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.articlenumber
66
dcterms.bibliographicCitation.doi
10.1038/s41467-018-07923-2
dcterms.bibliographicCitation.journaltitle
Nature Communications
dcterms.bibliographicCitation.volume
10
dcterms.bibliographicCitation.url
https://doi.org/10.1038/s41467-018-07923-2
refubium.affiliation
Biologie, Chemie, Pharmazie
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.isPartOf.issn
2041-1723