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

详细信息    查看全文

• 作者：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 Jr. ; Andrew Coop ; David J. Weber
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：January 28, 2016
• 年：2016
• 卷：59
• 期：2
• 页码：592-608
• 全文大小：872K
• ISSN：1520-4804

文摘

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.