2. Academic Validation
  3. PH-domain-binding inhibitors of nucleotide exchange factor BRAG2 disrupt Arf GTPase signaling

PH-domain-binding inhibitors of nucleotide exchange factor BRAG2 disrupt Arf GTPase signaling

  • Nat Chem Biol. 2019 Apr;15(4):358-366. doi: 10.1038/s41589-019-0228-3.
Agata Nawrotek 1 2,  Sarah Benabdi 1 2,  Supaporn Niyomchon 3 4 5,  Marie-Hélène Kryszke 1 2,  Christophe Ginestier 6,  Tatiana Cañeque 3 4 5,  Livia Tepshi 1 2,  Angelica Mariani 3 4 5,  Robert P St Onge 7,  Guri Giaever 8,  Corey Nislow 8,  Emmanuelle Charafe-Jauffret 6,  Raphaël Rodriguez 3 4 5,  Mahel Zeghouf 9 10,  Jacqueline Cherfils 11 12
Affiliations

Affiliations

  • 1 Laboratoire de Biologie et Pharmacologie Appliquée, Ecole normale supérieure Paris-Saclay, Cachan, France.
  • 2 CNRS, Cachan, France.
  • 3 Institut Curie, PSL Research University, Chemical Cell Biology Group, Paris, France.
  • 4 CNRS, Paris, France.
  • 5 INSERM, Paris, France.
  • 6 Université Aix-Marseille, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Epithelial Stem Cells and Cancer Team, Marseille, France.
  • 7 Genome Technology Center, Stanford School of Medicine, Stanford, CA, USA.
  • 8 Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
  • 9 Laboratoire de Biologie et Pharmacologie Appliquée, Ecole normale supérieure Paris-Saclay, Cachan, France. mahel.zeghouf@ens-paris-saclay.fr.
  • 10 CNRS, Cachan, France. mahel.zeghouf@ens-paris-saclay.fr.
  • 11 Laboratoire de Biologie et Pharmacologie Appliquée, Ecole normale supérieure Paris-Saclay, Cachan, France. jacqueline.cherfils@ens-paris-saclay.fr.
  • 12 CNRS, Cachan, France. jacqueline.cherfils@ens-paris-saclay.fr.
PMID: 30742123 DOI: 10.1038/s41589-019-0228-3
Abstract

Peripheral membrane proteins orchestrate many physiological and pathological processes, making regulation of their activities by small molecules highly desirable. However, they are often refractory to classical competitive inhibition. Here, we demonstrate that potent and selective inhibition of peripheral membrane proteins can be achieved by small molecules that target protein-membrane interactions by a noncompetitive mechanism. We show that the small molecule Bragsin inhibits BRAG2-mediated Arf GTPase activation in vitro in a manner that requires a membrane. In cells, Bragsin affects the trans-Golgi network in a BRAG2- and Arf-dependent manner. The crystal structure of the BRAG2-Bragsin complex and structure-activity relationship analysis reveal that Bragsin binds at the interface between the PH domain of BRAG2 and the lipid bilayer to render BRAG2 unable to activate lipidated Arf. Finally, Bragsin affects tumorsphere formation in breast Cancer cell lines. Bragsin thus pioneers a novel class of drugs that function by altering protein-membrane interactions without disruption.

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