Journal Article

PUBDB-2023-07400

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png From Tethered to Freestanding Stabilizers of 14‐3‐3 Protein‐Protein Interactions through Fragment Linking

Visser, E. J.Extern* ; Jaishankar, P. ; Sijbesma, E.Extern* ; Pennings, M. A. M. ; Vandenboorn, E. M. F. ; Guillory, X.Extern* ; Neitz, R. J. ; Morrow, J. ; Dutta, S. ; Renslo, A. R. (Corresponding author) ; Brunsveld, L. (Corresponding author) ; Arkin, M. R. (Corresponding author) ; Ottmann, C. (Corresponding author)Extern*

2023
Wiley-VCH Weinheim

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Please use a persistent id in citations: doi:10.1002/anie.202308004  doi:10.3204/PUBDB-2023-07400

Abstract: Small-molecule stabilization of protein-protein interactions (PPIs) is a promising strategy in chemical biology and drug discovery. However, the systematic discovery of PPI stabilizers remains a largely unmet challenge. Herein we report a fragment-linking approach targeting the interface of 14-3-3 and a peptide derived from the estrogen receptor alpha (ERα) protein. Two classes of fragments—a covalent and a noncovalent fragment—were co-crystallized and subsequently linked, resulting in a noncovalent hybrid molecule in which the original fragment interactions were largely conserved. Supported by 20 crystal structures, this initial hybrid molecule was further optimized, resulting in selective, 25-fold stabilization of the 14-3-3/ERα interaction. The high-resolution structures of both the single fragments, their co-crystal structures and those of the linked fragments document a feasible strategy to develop orthosteric PPI stabilizers by linking to an initial tethered fragment.

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Contributing Institute(s):

1. DOOR-User (DOOR ; HAS-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)

Experiment(s):

1. PETRA Beamline P11 (PETRA III)

Appears in the scientific report 2023

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Database coverage:
; ; ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; DEAL Wiley ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 15 ; Index Chemicus ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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