title: Small-Molecule Stabilization of the 14-3-3/Gab2 Protein-Protein Interaction (PPI) Interface.
abstract: Small-molecule modulation of protein-protein interactions (PPIs) is one of the most promising new areas in drug discovery. In the vast majority of cases only inhibition or disruption of PPIs is realized, whereas the complementary strategy of targeted stabilization of PPIs is clearly under-represented. Here, we report the example of a semi-synthetic natural product derivative--ISIR-005--that stabilizes the cancer-relevant interaction of the adaptor protein 14-3-3 and Gab2. The crystal structure of ISIR-005 in complex with 14-3-3 and the binding motif of Gab2 comprising two phosphorylation sites (Gab2pS210pT391) showed how the stabilizing molecule binds to the rim-of-the-interface of the protein complex. Only in the direct vicinity of 14-3-3/Gab2pT391 site is a pre-formed pocket occupied by ISIR-005; binding of the Gab2pS210 motif to 14-3-3 does not create an interface pocket suitable for the molecule. Accordingly, ISIR-005 only stabilizes the binding of the Gab2pT391 but not the Gab2pS210 site. This study represents structural and biochemical proof of the druggability of the 14-3-3/Gab2 PPI interface with important implications for the development of PPI stabilizers.
authors.affiliation: Department of Chemistry, University of Duisburg-Essen, Universitätstr. 7, 45141, Essen, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Bier
authors.affiliation: Department of Biomedical Engineering, Institute for Complex Molecular, Systems, Eindhoven University of Technology, P.O. Box 513, 5600 MB, Eindhoven, The Netherlands.
authors.forename: Maria
authors.initials: M
authors.lastname: Bartel
authors.affiliation: Institute of Molecular Medicine & Cell Research (IMMZ), Faculty of Medicine, University of Freiburg, Stefan-Meier-Str. 17, 79104, Freiburg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Sies
authors.affiliation: Institute of Molecular Medicine & Cell Research (IMMZ), Faculty of Medicine, University of Freiburg, Stefan-Meier-Str. 17, 79104, Freiburg, Germany.|Faculty of Biology, University of Freiburg, Schänzlestr. 1, 79104 Freiburg, Germany.|Spemann Graduate School of Biology & Medicine, University of Freiburg, Albertstr. 19A, 79104 Freiburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Halbach
authors.affiliation: The Institute of Scientific & Industrial Research, Osaka University, Osaka, 567-0047, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Higuchi
authors.affiliation: The Institute of Scientific & Industrial Research, Osaka University, Osaka, 567-0047, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Haranosono
authors.affiliation: Institute of Molecular Medicine & Cell Research (IMMZ), Faculty of Medicine, University of Freiburg, Stefan-Meier-Str. 17, 79104, Freiburg, Germany. tilman.brummer@mail.zbsa.uni-freiburg.de.|BIOSS: Centre for Biological Signaling Studies, University of Freiburg, Schänzlestr. 18, 79104 Freiburg, Germany. tilman.brummer@mail.zbsa.uni-freiburg.de.
authors.forename: Tilman
authors.initials: T
authors.lastname: Brummer
authors.affiliation: The Institute of Scientific & Industrial Research, Osaka University, Osaka, 567-0047, Japan. kato-n@sanken.osaka-u.ac.jp.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Kato
authors.affiliation: Department of Chemistry, University of Duisburg-Essen, Universitätstr. 7, 45141, Essen, Germany. christian.ottmann@uni-due.de, c.ottmann@tue.nl.|Department of Biomedical Engineering, Institute for Complex Molecular, Systems, Eindhoven University of Technology, P.O. Box 513, 5600 MB, Eindhoven, The Netherlands. christian.ottmann@uni-due.de, c.ottmann@tue.nl.
authors.forename: Christian
authors.initials: C
authors.lastname: Ottmann
mesh_terms: D048948:14-3-3 Proteins / Q000737:chemistry* / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000378:metabolism*; D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004224:Diterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D006027:Glycosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding / Q000187:drug effects; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D048948:14-3-3 Proteins; D048868:Adaptor Proteins, Signal Transducing; D001688:Biological Products; D004224:Diterpenes; C490895:GAB2 protein, human; D006027:Glycosides; C000612982:ISIR-005; D054852:Small Molecule Libraries
keywords: X-ray protein crystallography; natural products; protein-protein interactions; semi-synthesis; small molecules