# Allosteric Activation of GDP-Bound Ras Isoforms by Bisphenol Derivative Plasticisers  
[PERSON]  
1 Faculty of Chemistry and Biochemistry, Ruhr University of Bochum, Universitatsstr. 150, D-44780 Bochum, Germany; [EMAIL_ADDRESS] (M.S. ); [PERSON](O.S. ); [EMAIL_ADDRESS] (J.S. ); [PERSON]RESS] (K.K. ); [PERSON]SS] (X.Z. ); [EMAIL_ADDRESS] (C.H.) [PERSON]  
2  
[PERSON]  
1 Faculty of Chemistry and Biochemistry, Ruhr University of Bochum, Universitatsstr. 150, D-44780 Bochum, Germany; [EMAIL_ADDRESS] (M.S. ); [PERSON](O.S. ); [EMAIL_ADDRESS] (J.S. ); [PERSON]RESS] (K.K. ); [PERSON]SS] (X.Z. ); [EMAIL_ADDRESS] (C.H.) 3  
[PERSON]  
1 Faculty of Chemistry and Biochemistry, Ruhr University of Bochum, Universitatsstr. 150, D-44780 Bochum, Germany; [EMAIL_ADDRESS] (M.S. ); [PERSON](O.S. ); [PERSON]ESS] (J.S. ); [PERSON]RESS] (K.K. ); [PERSON]SS] (X.Z. ); [EMAIL_ADDRESS] (C.H.) 3  
Kus  
(Ras-like) G-proteins for its bound nucleotide [3; 4]. The Sos protein catalyses the rate-limiting and thus important step of restoring the level of activated, GTP-bound K-Ras4B in the cell, an essential protein isoform of the _ras_ gene family members [3]. Thus, the transition between these two GTPase states is catalysed by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) enhancing the intrinsic rate of GTP hydrolysis by small GTPases. Taken together, the GTPase cycle comprises inactive, GDP-bound and active, GTP-bound states that transmit extracellular within cells by interacting with numerous intracellular effector proteins. Therefore, this regulatory mechanism enables small GTPases to function as molecular switches in living cells. These key players of the intracellular signalling cascade have been in the focus of numerous cancer drug development initiatives for the more than two decades now [5; 6; 7; 8]. Previously, we have identified 4,4\({}^{\prime}\)-biphenol and Bisphenol A (BPA) as novel small molecular weight ligands for Rheb and K-Ras, respectively [9]. We have also shown that Bisphenol A (BPA)--but not Bisphenol S (BPS)--can interfere with the GEF-mediated nucleotide exchange from GDP to GTP [10]. Our study revealed for the first time that the plasticiser Bisphenol A is a K-Ras4B ligand, suggesting an entirely new mode of action for this endocrine disrupting chemical (EDC) and thereby supplementing the well-established estrogen receptor proteins as molecular targets of bisphenols [9]. Chemically, the family of bisphenols is characterised by an optionally substituted central carbon atom that is substituted by two hydroxyphenyl moieties. The most common member of this family is Bisphenol A (BPA, 4,4\({}^{\prime}\)-(propane-2,2-diyl)diphenol, CAS 80-05-7), whose central carbon carries two methyl and two phenolic groups. This compound class is in the center of both scientific and public discussion as to whether it can unsettle the normal activity of hormone receptors, because Bisphenol A is one of the chemicals humans are most frequently exposed to on a daily basis [11]. Food containers made out of polycarbonate plastics, such as baby bottles, and documents printed on thermal paper contain Bisphenol A, to name but a few [11]. Bisphenol A is suspected to cause cardiovascular diseases, breast and prostate cancers as well as neuronal disorders [11]. Bisphenol A has lately been replaced by its chemical analogue Bisphenol S (4,4\({}^{\prime}\)-Sulphonyldiphenol, CAS 80-09-1) due to public pressure and new governmental restrictions [10]. Yet, as previously found for BPA, BPS binds--albeit with a lower affinity--to a small ligand binding site between switch I and switch II of K-Ras4B, which is close to helix \(\alpha\)2 and the core \(\beta\)-sheets (\(\beta\)1-\(\beta\)3) [10]. However, in sharp contrast to Bisphenol A, Bisphenol S cannot interfere with the Sos-meditated nucleotide exchange of K-Ras4B.