Small Molecule Inhibitors of Ca(2+)-S100B Reveal Two Protein Conformations.

Publication Type:

Journal Article

Authors:

Cavalier, Michael C; Ansari, Mohd Imran; Pierce, Adam D; Wilder, Paul T; McKnight, Laura E; Raman, E Prabhu; Neau, David B; Bezawada, Padmavani; Alasady, Milad J; Charpentier, Thomas H; Varney, Kristen M; Toth, Eric A; MacKerell, Alexander D; Coop, Andrew; Weber, David J

Source:

J Med Chem, Volume 59, Issue 2, p.592-608 (2016)

Keywords:

Animals, Antineoplastic Agents, Cattle, Cell Line, Tumor, Crystallography, X-Ray, Drug Design, Humans, Models, Molecular, Pentamidine, Protein Conformation, Rats, S100 Calcium Binding Protein beta Subunit, Small Molecule Libraries, Structure-Activity Relationship, Tumor Suppressor Protein p53

Abstract:

<p>The drug pentamidine inhibits calcium-dependent complex formation with p53 ((Ca)S100B·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 (Ca)S100B·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 ((Ca)S100B·5a, (Ca)S100B·6b) a channel between sites 1 and 2 on S100B was occluded by residue Phe88, but for an asymmetric pentamidine analogue ((Ca)S100B·17), this same channel was open. The (Ca)S100B·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 (Ca)S100B, which will impact next generation (Ca)S100B·p53 inhibitor design.</p>

PDB: 
5DKN
Detector: 
Q315
Beamline: 
24-ID-E