Small-Molecule Stabilization of the 14-3-3/Gab2 Protein-Protein Interaction (PPI) Interface

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‐represente...

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Veröffentlicht in:	ChemMedChem Jg. 11; H. 8; S. 911 - 918
Hauptverfasser:	Bier, David, Bartel, Maria, Sies, Katharina, Halbach, Sebastian, Higuchi, Yusuke, Haranosono, Yu, Brummer, Tilman, Kato, Nobuo, Ottmann, Christian
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	Germany Blackwell Publishing Ltd 19.04.2016 Wiley Subscription Services, Inc
Schlagworte:	14-3-3 Proteins - chemistry 14-3-3 Proteins - metabolism Adaptor Proteins, Signal Transducing - chemistry Adaptor Proteins, Signal Transducing - metabolism Biological Products - chemical synthesis Biological Products - chemistry Biological Products - pharmacology Crystal structure Crystallography, X-Ray Diterpenes - chemical synthesis Diterpenes - chemistry Diterpenes - pharmacology Dose-Response Relationship, Drug Drug Stability Glycosides - chemical synthesis Glycosides - chemistry Glycosides - pharmacology Humans Models, Molecular Molecular Conformation natural products Protein Binding - drug effects protein-protein interactions Proteins semi-synthesis Small Molecule Libraries - chemical synthesis Small Molecule Libraries - chemistry Small Molecule Libraries - pharmacology small molecules Structure-Activity Relationship Tumor Cells, Cultured X-ray protein crystallography natural products semi-synthesis small molecules X-ray protein crystallography protein-protein interactions
ISSN:	1860-7179, 1860-7187, 1860-7187
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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. A stabilizing influence: We have identified a semi‐synthetic, natural product protein–protein interaction (PPI) stabilizer that enhances the binding of the adapter protein 14‐3‐3 to oncogenic Gab2. Stabilization of this PPI is expected to attenuate the pro‐oncogenic activity of Gab2. Our molecule, ISIR‐005, represents chemical proof‐of‐principle for the druggability of the 14‐3‐3/Gab2 interface.
AbstractList	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. 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.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. 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. A stabilizing influence: We have identified a semi‐synthetic, natural product protein–protein interaction (PPI) stabilizer that enhances the binding of the adapter protein 14‐3‐3 to oncogenic Gab2. Stabilization of this PPI is expected to attenuate the pro‐oncogenic activity of Gab2. Our molecule, ISIR‐005, represents chemical proof‐of‐principle for the druggability of the 14‐3‐3/Gab2 interface.
Author	Haranosono, Yu Brummer, Tilman Kato, Nobuo Sies, Katharina Bartel, Maria Bier, David Ottmann, Christian Halbach, Sebastian Higuchi, Yusuke
Author_xml	– sequence: 1 givenname: David surname: Bier fullname: Bier, David organization: Department of Chemistry, University of Duisburg-Essen, Universitätstr. 7, 45141, Essen, Germany – sequence: 2 givenname: Maria surname: Bartel fullname: Bartel, Maria organization: Department of Biomedical Engineering, Institute for Complex Molecular, Systems, Eindhoven University of Technology, P.O. Box 513, 5600 MB, Eindhoven, The Netherlands – sequence: 3 givenname: Katharina surname: Sies fullname: Sies, Katharina organization: Institute of Molecular Medicine & Cell Research (IMMZ), Faculty of Medicine, University of Freiburg, Stefan-Meier-Str. 17, 79104, Freiburg, Germany – sequence: 4 givenname: Sebastian surname: Halbach fullname: Halbach, Sebastian organization: Institute of Molecular Medicine & Cell Research (IMMZ), Faculty of Medicine, University of Freiburg, Stefan-Meier-Str. 17, 79104, Freiburg, Germany – sequence: 5 givenname: Yusuke surname: Higuchi fullname: Higuchi, Yusuke organization: The Institute of Scientific & Industrial Research, Osaka University, 567-0047, Osaka, Japan – sequence: 6 givenname: Yu surname: Haranosono fullname: Haranosono, Yu organization: The Institute of Scientific & Industrial Research, Osaka University, 567-0047, Osaka, Japan – sequence: 7 givenname: Tilman surname: Brummer fullname: Brummer, Tilman email: tilman.brummer@mail.zbsa.uni-freiburg.de organization: Institute of Molecular Medicine & Cell Research (IMMZ), Faculty of Medicine, University of Freiburg, Stefan-Meier-Str. 17, 79104, Freiburg, Germany – sequence: 8 givenname: Nobuo surname: Kato fullname: Kato, Nobuo email: kato-n@sanken.osaka-u.ac.jp organization: The Institute of Scientific & Industrial Research, Osaka University, 567-0047, Osaka, Japan – sequence: 9 givenname: Christian surname: Ottmann fullname: Ottmann, Christian email: christian.ottmann@uni-due.de, c.ottmann@tue.nl organization: Department of Chemistry, University of Duisburg-Essen, Universitätstr. 7, 45141, Essen, Germany
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Snippet	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... 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...
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SubjectTerms	14-3-3 Proteins - chemistry 14-3-3 Proteins - metabolism Adaptor Proteins, Signal Transducing - chemistry Adaptor Proteins, Signal Transducing - metabolism Biological Products - chemical synthesis Biological Products - chemistry Biological Products - pharmacology Crystal structure Crystallography, X-Ray Diterpenes - chemical synthesis Diterpenes - chemistry Diterpenes - pharmacology Dose-Response Relationship, Drug Drug Stability Glycosides - chemical synthesis Glycosides - chemistry Glycosides - pharmacology Humans Models, Molecular Molecular Conformation natural products Protein Binding - drug effects protein-protein interactions Proteins semi-synthesis Small Molecule Libraries - chemical synthesis Small Molecule Libraries - chemistry Small Molecule Libraries - pharmacology small molecules Structure-Activity Relationship Tumor Cells, Cultured X-ray protein crystallography
Title	Small-Molecule Stabilization of the 14-3-3/Gab2 Protein-Protein Interaction (PPI) Interface
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