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

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TitleSmall Molecule Inhibitors of Ca(2+)-S100B Reveal Two Protein Conformations.
Publication TypeJournal Article
Year of Publication2016
AuthorsCavalier, MC, Ansari, MImran, Pierce, AD, Wilder, PT, McKnight, LE, E Raman, P, Neau, DB, Bezawada, P, Alasady, MJ, Charpentier, TH, Varney, KM, Toth, EA, Mackerell, AD, Coop, A, Weber, DJ
JournalJ Med Chem
Volume59
Issue2
Pagination592-608
Date Published2016 Jan 28
ISSN1520-4804
KeywordsAnimals, 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

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.

DOI10.1021/acs.jmedchem.5b01369
Alternate JournalJ. Med. Chem.
PubMed ID26727270
PubMed Central IDPMC4732916
Grant ListR01 GM070855 / GM / NIGMS NIH HHS / United States
S10 RR023447 / RR / NCRR NIH HHS / United States
P41 GM103403 / GM / NIGMS NIH HHS / United States
S10 RR029601 / RR / NCRR NIH HHS / United States
S10 RR15741 / RR / NCRR NIH HHS / United States
S10 RR23447 / RR / NCRR NIH HHS / United States
R01 CA107331 / CA / NCI NIH HHS / United States
GM58888 / GM / NIGMS NIH HHS / United States
S10 RR10441 / RR / NCRR NIH HHS / United States
GM070855 / GM / NIGMS NIH HHS / United States
CA107331 / CA / NCI NIH HHS / United States
P41GM103393 / GM / NIGMS NIH HHS / United States
S10 RR031729 / RR / NCRR NIH HHS / United States
T32 CA154274 / CA / NCI NIH HHS / United States
S10 RR16812 / RR / NCRR NIH HHS / United States
R01 GM058888 / GM / NIGMS NIH HHS / United States
P41 GM103393 / GM / NIGMS NIH HHS / United States