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Small molecules bound to unique sites in the target protein binding cleft of calcium-bound S100B as characterized by nuclear magnetic resonance and X-ray crystallography.

Charpentier TH, Wilder PT, Liriano MA, Varney KM, Zhong S, Coop A, Pozharski E, MacKerell AD, Toth EA, Weber DJ
Biochemistry 48 6202-12 (2009)
Related entries: 3gk2, 3gk4

Cited: 26 times
EuropePMC logo PMID: 19469484

Abstract

Structural studies are part of a rational drug design program aimed at inhibiting the S100B-p53 interaction and restoring wild-type p53 function in malignant melanoma. To this end, structures of three compounds (SBi132, SBi1279, and SBi523) bound to Ca(2+)-S100B were determined by X-ray crystallography at 2.10 A (R(free) = 0.257), 1.98 A (R(free) = 0.281), and 1.90 A (R(free) = 0.228) resolution, respectively. Upon comparison, SBi132, SBi279, and SBi523 were found to bind in distinct locations and orientations within the hydrophobic target binding pocket of Ca(2+)-S100B with minimal structural changes observed for the protein upon complex formation with each compound. Specifically, SBi132 binds nearby residues in loop 2 (His-42, Phe-43, and Leu-44) and helix 4 (Phe-76, Met-79, Ile-80, Ala-83, Cys-84, Phe-87, and Phe-88), whereas SBi523 interacts with a separate site defined by residues within loop 2 (Ser-41, His-42, Phe-43, Leu-44, Glu-45, and Glu-46) and one residue on helix 4 (Phe-87). The SBi279 binding site on Ca(2+)-S100B overlaps the SBi132 and SBi523 sites and contacts residues in both loop 2 (Ser-41, His-42, Phe-43, Leu-44, and Glu-45) and helix 4 (Ile-80, Ala-83, Cys-84, Phe-87, and Phe-88). NMR data, including saturation transfer difference (STD) and (15)N backbone and (13)C side chain chemical shift perturbations, were consistent with the X-ray crystal structures and demonstrated the relevance of all three small molecule-S100B complexes in solution. The discovery that SBi132, SBi279, and SBi523 bind to proximal sites on Ca(2+)-S100B could be useful for the development of a new class of molecule(s) that interacts with one or more of these binding sites simultaneously, thereby yielding novel tight binding inhibitors specific for blocking protein-protein interactions involving S100B.

Reviews - 3gk1 mentioned but not cited (1)

  1. The evolution of S100B inhibitors for the treatment of malignant melanoma. Hartman KG, McKnight LE, Liriano MA, Weber DJ. Future Med Chem 5 97-109 (2013)

Articles - 3gk1 mentioned but not cited (8)

  1. Small molecules bound to unique sites in the target protein binding cleft of calcium-bound S100B as characterized by nuclear magnetic resonance and X-ray crystallography. Charpentier TH, Wilder PT, Liriano MA, Varney KM, Zhong S, Coop A, Pozharski E, MacKerell AD, Toth EA, Weber DJ. Biochemistry 48 6202-6212 (2009)
  2. Structural properties of non-traditional drug targets present new challenges for virtual screening. Gowthaman R, Deeds EJ, Karanicolas J. J Chem Inf Model 53 2073-2081 (2013)
  3. Multiple Evolutionary Origins of Ubiquitous Cu2+ and Zn2+ Binding in the S100 Protein Family. Wheeler LC, Donor MT, Prell JS, Harms MJ. PLoS One 11 e0164740 (2016)
  4. Enhancements to the Rosetta Energy Function Enable Improved Identification of Small Molecules that Inhibit Protein-Protein Interactions. Bazzoli A, Kelow SP, Karanicolas J. PLoS One 10 e0140359 (2015)
  5. What can we learn from the evolution of protein-ligand interactions to aid the design of new therapeutics? Higueruelo AP, Schreyer A, Bickerton GR, Blundell TL, Pitt WR. PLoS One 7 e51742 (2012)
  6. Conservation of Specificity in Two Low-Specificity Proteins. Wheeler LC, Anderson JA, Morrison AJ, Wong CE, Harms MJ. Biochemistry 57 684-695 (2018)
  7. Small Molecule Inhibitors of Ca(2+)-S100B Reveal Two Protein Conformations. Cavalier MC, Ansari MI, Pierce AD, Wilder PT, McKnight LE, Raman EP, Neau DB, Bezawada P, Alasady MJ, Charpentier TH, Varney KM, Toth EA, MacKerell AD, Coop A, Weber DJ. J Med Chem 59 592-608 (2016)
  8. Novel protein-inhibitor interactions in site 3 of Ca(2+)-bound S100B as discovered by X-ray crystallography. Cavalier MC, Melville Z, Aligholizadeh E, Raman EP, Yu W, Fang L, Alasady M, Pierce AD, Wilder PT, MacKerell AD, Weber DJ. Acta Crystallogr D Struct Biol 72 753-760 (2016)


Reviews citing this publication (4)

  1. Functions of S100 proteins. Donato R, Cannon BR, Sorci G, Riuzzi F, Hsu K, Weber DJ, Geczy CL. Curr Mol Med 13 24-57 (2013)
  2. S100 proteins in rheumatic diseases. Austermann J, Spiekermann C, Roth J. Nat Rev Rheumatol 14 528-541 (2018)
  3. Binding of transition metals to S100 proteins. Gilston BA, Skaar EP, Chazin WJ. Sci China Life Sci 59 792-801 (2016)
  4. Molecular dynamic simulation insights into the normal state and restoration of p53 function. Fu T, Min H, Xu Y, Chen J, Li G. Int J Mol Sci 13 9709-9740 (2012)

Articles citing this publication (13)

  1. Fluorescence polarization assays in high-throughput screening and drug discovery: a review. Hall MD, Yasgar A, Peryea T, Braisted JC, Jadhav A, Simeonov A, Coussens NP. Methods Appl Fluoresc 4 022001 (2016)
  2. Modulating protein-protein interactions with small molecules: the importance of binding hotspots. Thangudu RR, Bryant SH, Panchenko AR, Madej T. J Mol Biol 415 443-453 (2012)
  3. The Calcium-Dependent Interaction of S100B with Its Protein Targets. Zimmer DB, Weber DJ. Cardiovasc Psychiatry Neurol 2010 728052 (2010)
  4. Covalent small molecule inhibitors of Ca(2+)-bound S100B. Cavalier MC, Pierce AD, Wilder PT, Alasady MJ, Hartman KG, Neau DB, Foley TL, Jadhav A, Maloney DJ, Simeonov A, Toth EA, Weber DJ. Biochemistry 53 6628-6640 (2014)
  5. In vitro screening and structural characterization of inhibitors of the S100B-p53 interaction. Wilder PT, Charpentier TH, Liriano MA, Gianni K, Varney KM, Pozharski E, Coop A, Toth EA, Mackerell AD, Weber DJ. Int J High Throughput Screen 2010 109-126 (2010)
  6. In vivo screening of S100B inhibitors for melanoma therapy. Zimmer DB, Lapidus RG, Weber DJ. Methods Mol Biol 963 303-317 (2013)
  7. Fragmenting the S100B-p53 interaction: combined virtual/biophysical screening approaches to identify ligands. Agamennone M, Cesari L, Lalli D, Turlizzi E, Del Conte R, Turano P, Mangani S, Padova A. ChemMedChem 5 428-435 (2010)
  8. Identification of small-molecule inhibitors of the human S100B-p53 interaction and evaluation of their activity in human melanoma cells. Yoshimura C, Miyafusa T, Tsumoto K. Bioorg Med Chem 21 1109-1115 (2013)
  9. NMR-guided molecular docking of a protein-peptide complex based on ant colony optimization. Korb O, Möller HM, Exner TE. ChemMedChem 5 1001-1006 (2010)
  10. X-ray crystal structure of human calcium-bound S100A1. Melville Z, Aligholizadeh E, McKnight LE, Weber DJ, Pozharski E, Weber DJ. Acta Crystallogr F Struct Biol Commun 73 215-221 (2017)
  11. Probing the Effect of Halogen Substituents (Br, Cl, and F) on the Non-covalent Interactions in 1-(Adamantan-1-yl)-3-arylthiourea Derivatives: A Theoretical Study. Al-Wahaibi LH, Grandhi DS, Tawfik SS, Al-Shaalan NH, Elmorsy MA, El-Emam AA, Percino MJ, Thamotharan S. ACS Omega 6 4816-4830 (2021)
  12. Structural Basis for S100B Interaction with its Target Proteins. Prez KD, Fan L. J Mol Genet Med 12 366 (2018)
  13. The calcium-binding protein S100B reduces IL6 production in malignant melanoma via inhibition of RSK cellular signaling. Alasady MJ, Terry AR, Pierce AD, Cavalier MC, Blaha CS, Adipietro KA, Wilder PT, Weber DJ, Hay N. PLoS One 16 e0256238 (2021)


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