Novel protein–inhibitor interactions in site 3 of Ca²⁺-bound S100B as discovered by X-ray crystallography

Abstract

Structure-based drug discovery is under way to identify and develop small-molecule S100B inhibitors (SBiXs). Such inhibitors have therapeutic potential for treating malignant melanoma, since high levels of S100B downregulate wild-type p53 tumor suppressor function in this cancer. Computational and X-ray crystallographic studies of two S100B-SBiX complexes are described, and both compounds (apomorphine hydrochloride and ethidium bromide) occupy an area of the S100B hydrophobic cleft which is termed site 3. These data also reveal novel protein-inhibitor interactions which can be used in future drug-design studies to improve SBiX affinity and specificity. Of particular interest, apomorphine hydrochloride showed S100B-dependent killing in melanoma cell assays, although the efficacy exceeds its affinity for S100B and implicates possible off-target contributions. Because there are no structural data available for compounds occupying site 3 alone, these studies contribute towards the structure-based approach to targeting S100B by including interactions with residues in site 3 of S100B.

The S100B story: from biomarker to active factor in neural injury

“…It may be relevant in this respect that the search for additional similarly useful molecules is being actively pursued via a structure‐based approach (Cavalier et al . ). More recently, even extracts from traditional remedies have been used in an attempt to block the protein (Qin et al .…”

“…While the mechanism of action of arundic acid, which inhibits astrocytic S100B synthesis, has not been clearly elucidated, both pentamidine and TRTK12 peptide are known to block the interaction between S100B and the transcription factor p53 (Charpentier et al 2010;Hartman et al 2013). It may be relevant in this respect that the search for additional similarly useful molecules is being actively pursued via a structure-based approach (Cavalier et al 2016). More recently, even extracts from traditional remedies have been used in an attempt to block the protein (Qin et al 2018).…”

“…However, the putative role played by the S100B‐p53 interaction in melanoma processes has stimulated the development of research programs aimed at individuating molecules able to interfere with this interaction (Cavalier et al . ), which might finally result of wider utility.…”

“…While the neuroectodermal origin of melanoma may suggest a linkage between the relevance of S100B in this disease and the numerous neural disorders in which it is involved, at present a unifying scenario has not been delineated. However, the putative role played by the S100B-p53 interaction in melanoma processes has stimulated the development of research programs aimed at individuating molecules able to interfere with this interaction (Cavalier et al 2016), which might finally result of wider utility.…”

The Zn2+ and Ca2+‐binding S100B and S100A1 proteins: beyond the myths

“…This model should help direct further structural studies to resolve the stoichiometry and dynamics of the interaction of S100B with other proposed target proteins. It may also facilitate the design of new chemical inhibitors for therapeutic purposes (Yoshimura, Miyafusa & Tsumoto, ; Cavalier et al ., ,b; Bresnick, ). Finally, a chaperone‐associated function for intracellular S100B is discussed.…”