The Gαi-GIV binding interface is a druggable protein-protein interaction

Abstract Heterotrimeric G proteins are usually activated by the guanine-nucleotide exchange factor (GEF) activity of GPCRs. However, some non-receptor proteins are also GEFs. GIV (a.k.a Girdin) was the first non-receptor protein for which the GEF activity was ascribed to a well-defined protein seque...

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Autores principales:	Vincent DiGiacomo, Alain Ibáñez de Opakua, Maria P. Papakonstantinou, Lien T. Nguyen, Nekane Merino, Juan B. Blanco-Canosa, Francisco J. Blanco, Mikel Garcia-Marcos
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b433a7a3090546b08a7b912bf7b9d6f6
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spelling	oai:doaj.org-article:b433a7a3090546b08a7b912bf7b9d6f62021-12-02T16:05:58ZThe Gαi-GIV binding interface is a druggable protein-protein interaction10.1038/s41598-017-08829-72045-2322https://doaj.org/article/b433a7a3090546b08a7b912bf7b9d6f62017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08829-7https://doaj.org/toc/2045-2322Abstract Heterotrimeric G proteins are usually activated by the guanine-nucleotide exchange factor (GEF) activity of GPCRs. However, some non-receptor proteins are also GEFs. GIV (a.k.a Girdin) was the first non-receptor protein for which the GEF activity was ascribed to a well-defined protein sequence that directly binds Gαi. GIV expression promotes metastasis and disruption of its binding to Gαi blunts the pro-metastatic behavior of cancer cells. Although this suggests that inhibition of the Gαi-GIV interaction is a promising therapeutic strategy, protein-protein interactions (PPIs) are considered poorly “druggable” targets requiring case-by-case validation. Here, we set out to investigate whether Gαi-GIV is a druggable PPI. We tested a collection of >1,000 compounds on the Gαi-GIV PPI by in silico ligand screening and separately by a chemical high-throughput screening (HTS) assay. Two hits, ATA and NF023, obtained in both screens were confirmed in secondary HTS and low-throughput assays. The binding site of NF023, identified by NMR spectroscopy and biochemical assays, overlaps with the Gαi-GIV interface. Importantly, NF023 did not disrupt Gαi-Gβγ binding, indicating its specificity toward Gαi-GIV. This work establishes the Gαi-GIV PPI as a druggable target and sets the conceptual and technical framework for the discovery of novel inhibitors of this PPI.Vincent DiGiacomoAlain Ibáñez de OpakuaMaria P. PapakonstantinouLien T. NguyenNekane MerinoJuan B. Blanco-CanosaFrancisco J. BlancoMikel Garcia-MarcosNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-17 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Vincent DiGiacomo Alain Ibáñez de Opakua Maria P. Papakonstantinou Lien T. Nguyen Nekane Merino Juan B. Blanco-Canosa Francisco J. Blanco Mikel Garcia-Marcos The Gαi-GIV binding interface is a druggable protein-protein interaction
description	Abstract Heterotrimeric G proteins are usually activated by the guanine-nucleotide exchange factor (GEF) activity of GPCRs. However, some non-receptor proteins are also GEFs. GIV (a.k.a Girdin) was the first non-receptor protein for which the GEF activity was ascribed to a well-defined protein sequence that directly binds Gαi. GIV expression promotes metastasis and disruption of its binding to Gαi blunts the pro-metastatic behavior of cancer cells. Although this suggests that inhibition of the Gαi-GIV interaction is a promising therapeutic strategy, protein-protein interactions (PPIs) are considered poorly “druggable” targets requiring case-by-case validation. Here, we set out to investigate whether Gαi-GIV is a druggable PPI. We tested a collection of >1,000 compounds on the Gαi-GIV PPI by in silico ligand screening and separately by a chemical high-throughput screening (HTS) assay. Two hits, ATA and NF023, obtained in both screens were confirmed in secondary HTS and low-throughput assays. The binding site of NF023, identified by NMR spectroscopy and biochemical assays, overlaps with the Gαi-GIV interface. Importantly, NF023 did not disrupt Gαi-Gβγ binding, indicating its specificity toward Gαi-GIV. This work establishes the Gαi-GIV PPI as a druggable target and sets the conceptual and technical framework for the discovery of novel inhibitors of this PPI.
format	article
author	Vincent DiGiacomo Alain Ibáñez de Opakua Maria P. Papakonstantinou Lien T. Nguyen Nekane Merino Juan B. Blanco-Canosa Francisco J. Blanco Mikel Garcia-Marcos
author_facet	Vincent DiGiacomo Alain Ibáñez de Opakua Maria P. Papakonstantinou Lien T. Nguyen Nekane Merino Juan B. Blanco-Canosa Francisco J. Blanco Mikel Garcia-Marcos
author_sort	Vincent DiGiacomo
title	The Gαi-GIV binding interface is a druggable protein-protein interaction
title_short	The Gαi-GIV binding interface is a druggable protein-protein interaction
title_full	The Gαi-GIV binding interface is a druggable protein-protein interaction
title_fullStr	The Gαi-GIV binding interface is a druggable protein-protein interaction
title_full_unstemmed	The Gαi-GIV binding interface is a druggable protein-protein interaction
title_sort	gαi-giv binding interface is a druggable protein-protein interaction
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/b433a7a3090546b08a7b912bf7b9d6f6
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The Gαi-GIV binding interface is a druggable protein-protein interaction

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