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.

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-

SUBMITTER: Charpentier TH 

PROVIDER: S-EPMC2804263 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature