title: Bisphenol A binds to Ras proteins and competes with guanine nucleotide exchange: implications for GTPase-selective antagonists.
abstract: We show for the first time that bisphenol A (10) has the capacity to interact directly with K-Ras and that Rheb weakly binds to bisphenol A (10) and 4,4'-biphenol derivatives. We have characterized these interactions at atomic resolution suggesting that these compounds sterically interfere with the Sos-mediated nucleotide exchange in H- and K-Ras. We show that 4,4'-biphenol (5) selectively inhibits Rheb signaling and induces cell death suggesting that this compound might be a novel candidate for treatment of tuberous sclerosis-mediated tumor growth. Our results propose a new mode of action for bisphenol A (10) that advocates a reduced exposure to this compound in our environment. Our data may lay the foundation for the future design of GTPase-selective antagonists with higher affinity to benefit of the treatment of cancer because K-Ras inhibition is regarded to be a promising strategy with a potential therapeutic window for targeting Sos in Ras-driven tumors.
authors.affiliation: Faculty of Chemistry and Biochemistry, Ruhr University of Bochum , Universitätsstraße 150, D-44780 Bochum, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Schöpel
authors.forename: Katharina F G
authors.initials: KF
authors.lastname: Jockers
authors.forename: Peter M
authors.initials: PM
authors.lastname: Düppe
authors.forename: Jasmin
authors.initials: J
authors.lastname: Autzen
authors.forename: Veena N
authors.initials: VN
authors.lastname: Potheraveedu
authors.forename: Semra
authors.initials: S
authors.lastname: Ince
authors.forename: King Tuo
authors.initials: KT
authors.lastname: Yip
authors.forename: Rolf
authors.initials: R
authors.lastname: Heumann
authors.forename: Christian
authors.initials: C
authors.lastname: Herrmann
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scherkenbeck
authors.forename: Raphael
authors.initials: R
authors.lastname: Stoll
mesh_terms: D001559:Benzhydryl Compounds / Q000737:chemistry / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006153:Guanosine Diphosphate / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D020559:Monomeric GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D000076205:Ras Homolog Enriched in Brain Protein; D013014:SOS Response, Genetics / Q000187:drug effects; D018631:ras Proteins / Q000378:metabolism*; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D001713:Biphenyl Compounds; D020558:GTP Phosphohydrolases; D020662:Guanine Nucleotide Exchange Factors; D006153:Guanosine Diphosphate; D020559:Monomeric GTP-Binding Proteins; D009479:Neuropeptides; D010636:Phenols; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D000076205:Ras Homolog Enriched in Brain Protein; D018631:ras Proteins; C117307:KRAS protein, human; C490211:RHEB protein, human; C006780:bisphenol A; D000098826:Bisphenol A Compounds; C027439:4,4'-dihydroxybiphenyl