title: GTP is an allosteric modulator of the interaction between the guanylate-binding protein 1 and the prosurvival kinase PIM1.
abstract: GBP1 and PIM1 are known to interact with a molar ratio 1:1. GBP1:PIM1 binding initiates a signaling pathway that induces resistance to common chemotherapeutics such as paclitaxel. Since GBP1 is a large GTPase which undergoes conformational changes in a nucleotide-dependent manner, we investigated the effect of GTP/GDP binding on GBP1:PIM1 interaction by using computational and biological studies. It resulted that only GTP decreases the formation of the GBP1:PIM1 complex through an allosteric mechanism, putting the bases for the identification of new compounds potentially able to revert resistance to paclitaxel.
authors: Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano 49, I-80131 Napoli, Italy.
authors: Marco
authors: M
authors: Persico
authors: Laboratory of Molecular Oncology, Jean Paul II Research Foundation, Campobasso 86100, Italy.
authors: Lella
authors: L
authors: Petrella
authors: Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano 49, I-80131 Napoli, Italy.
authors: Nausicaa
authors: N
authors: Orteca
authors: Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano 49, I-80131 Napoli, Italy.
authors: Antonio
authors: A
authors: Di Dato
authors: Danbury Hospital Research Institute, Danbury, CT 06810, USA.
authors: Marisa
authors: M
authors: Mariani
authors: Danbury Hospital Research Institute, Danbury, CT 06810, USA.
authors: Mirko
authors: M
authors: Andreoli
authors: Catholic University of the Sacred Heart, Department of Obstetrics and Gynaecology, Rome, Italy.
authors: Marta
authors: M
authors: De Donato
authors: Catholic University of the Sacred Heart, Department of Obstetrics and Gynaecology, Rome, Italy.
authors: Giovanni
authors: G
authors: Scambia
authors: Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano 49, I-80131 Napoli, Italy.
authors: Ettore
authors: E
authors: Novellino
authors: Danbury Hospital Research Institute, Danbury, CT 06810, USA. Electronic address: cristiano.ferlini@danhosp.org.
authors: Cristiano
authors: C
authors: Ferlini
authors: Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano 49, I-80131 Napoli, Italy. Electronic address: caterina.fattorusso@unina.it.
authors: Caterina
authors: C
authors: Fattorusso
mesh_terms: D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry; D001665:Binding Sites; D019008:Drug Resistance, Neoplasm; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000737:chemistry* / Q000235:genetics; D015870:Gene Expression; D006153:Guanosine Diphosphate / Q000737:chemistry*; D006160:Guanosine Triphosphate / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000235:genetics; D017239:Paclitaxel / Q000737:chemistry; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051573:Proto-Oncogene Proteins c-pim-1 / Q000737:chemistry* / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D013816:Thermodynamics
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C490287:GBP1 protein, human; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1; D019204:GTP-Binding Proteins; D017239:Paclitaxel
keywords: Allosteric inhibition of protein protein interaction; GTPase activity; Human guanylate-binding protein 1; Paclitaxel resistance; Protein conformational changes