3GK4

X-ray structure of bovine SBi523,Ca(2+)-S100B

Summary for 3GK4

• Entry DOI: 10.2210/pdb3gk4/pdb
• Related: 1DT7 1MHO 3CR2 3CR4 3CR5 3GK1 3GK2
• Descriptor: Protein S100-B, CALCIUM ION, ethyl 5-{[(1R)-1-(ethoxycarbonyl)-2-oxopropyl]sulfanyl}-1,2-dihydro[1,2,3]triazolo[1,5-a]quinazoline-3-carboxylate, ... (4 entities in total)
• Functional Keywords: ef hand, alpha helical, metal-binding, nucleus, metal binding protein
• Biological source: Bos taurus (bovine,cow,domestic cattle,domestic cow)
• Cellular location: Cytoplasm: P02638
• Total number of polymer chains: 1
• Total formula weight: 11166.57

Authors

Charpentier, T.H.,Weber, D.J.,Toth, E.A. (deposition date: 2009-03-09, release date: 2009-06-09, Last modification date: 2023-09-06)

Primary citation

Charpentier, T.H.,Wilder, P.T.,Liriano, M.A.,Varney, K.M.,Zhong, S.,Coop, A.,Pozharski, E.,MacKerell, A.D.,Toth, E.A.,Weber, D.J.
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.
Biochemistry, 48:6202-6212, 2009

PubMed 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.

PubMed: 19469484
DOI: 10.1021/bi9005754

Experimental method

X-RAY DIFFRACTION (1.9 Å)