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Title: Small molecule inhibitors of Ca2+-S100B reveal two protein conformations

Journal Article · · Journal of Medicinal Chemistry
 [1];  [2];  [1];  [1];  [1];  [2];  [3];  [2];  [1];  [1];  [1];  [4];  [5];  [5];  [1]
  1. Univ. of Maryland School of Medicine, Baltimore, MD (United States)
  2. Univ. of Maryland, Baltimore, MD (United States)
  3. NE-CAT, Argonne, IL (United States)
  4. Univ. of Maryland School of Medicine, Baltimore, MD (United States); Institute for Bioscience and Biotechnology Research, Rockville, MD (United States)
  5. Univ. of Maryland, Baltimore, MD (United States); Univ. of Maryland School of Medicine, Baltimore, MD (United States)
+ Show Author Affiliations

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 in this study 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. Finally, 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.

Research Organization:
Univ. of Maryland, Baltimore, MD (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER)
Grant/Contract Number:
AC02-06CH11357; AC02-76SF00515
OSTI ID:
1344914
Journal Information:
Journal of Medicinal Chemistry, Vol. 59, Issue 2; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 13 works
Citation information provided by
Web of Science

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Cited By (4)

The Zn 2+ and Ca 2+ ‐binding S100B and S100A1 proteins: beyond the myths journal February 2020
Designed mono- and di-covalent inhibitors trap modeled functional motions for Trypanosoma cruzi proline racemase in crystallography journal October 2018
BindingDB Entry 50047064: Small Molecule Inhibitors of Ca(2+)-S100B Reveal Two Protein Conformations. dataset January 2017
Structural Basis for S100B Interaction with its Target Proteins journal January 2018

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