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Small Molecule Inhibitors of Ca2+-S100B Reveal Two Protein Conformations

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journal contribution
posted on 28.01.2016, 00:00 by Michael C. Cavalier, Mohd. Imran Ansari, Adam D. Pierce, Paul T. Wilder, Laura E. McKnight, E. Prabhu Raman, David B. Neau, Padmavani Bezawada, Milad J. Alasady, Thomas H. Charpentier, Kristen M. Varney, Eric A. Toth, Alexander D. MacKerell, Andrew Coop, David J. Weber
The drug pentamidine inhibits calcium-dependent complex formation with p53 (CaS100B·p53) in malignant melanoma (MM) and restores p53 tumor suppressor activity in vivo. However, off-target effects associated with this drug were problematic in MM patients. Structure–activity relationship (SAR) studies were therefore completed here with 23 pentamidine analogues, and X-ray structures of CaS100B·inhibitor complexes revealed that the C-terminus of S100B adopts two different conformations, with location of Phe87 and Phe88 being the distinguishing feature and termed the “FF-gate”. For symmetric pentamidine analogues (CaS100B·5a, CaS100B·6b) a channel between sites 1 and 2 on S100B was occluded by residue Phe88, but for an asymmetric pentamidine analogue (CaS100B·17), this same channel was open. The CaS100B·17 structure illustrates, for the first time, a pentamidine analog capable of binding the “open” form of the “FF-gate” and provides a means to block all three “hot spots” on CaS100B, which will impact next generation CaS100B·p53 inhibitor design.