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The 3D structures of Ca 2+ ‐S100B in Zn 2+ ‐ and pentamidine‐bound complexes as determined by X‐ray crystallography
Author(s) -
Charpentier Thomas Henry,
Wilder Paul T,
Varney Kristen M,
Toth Eric A,
Weber David J
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a630-a
Subject(s) - pentamidine , crystallography , chemistry , dimer , molecule , crystal structure , binding site , intermolecular force , x ray crystallography , stereochemistry , diffraction , physics , biochemistry , optics , pneumonia , archaeology , organic chemistry , history
Structural studies are part of a rational drug design program underway to inhibit the S100B‐p53 interaction and restore p53 function in malignant melanoma. Specifically, co‐crystals of Zn 2+ ‐Ca 2+ ‐S100B and pentamidine‐ Zn 2+ ‐Ca 2+ ‐S100B diffracted to 2.35 and 2.2 Å in the space groups C2221 and P41212, respectively. Both structures were solved by X‐ray crystallography using molecular replacement techniques to give 3D structures with R free values of 0.277 and 0.281, respectively. Pentamidine binds adjacent to Zn 2+ in a small pocket located at the S100B dimer interface and the electron density is more readily defined for the inhibitor when Zn 2+ is present. The location of pentamidine in the crystal structure is consistent with NMR data including intermolecular NOE correlations, saturation transfer difference (STD), and chemical shift perturbations. The location of pentamidine nearby the Zn 2+ site on S100B represents a new small molecule binding site, adjacent to the p53 binding site, which could be important for developing inhibitors of the S100B‐p53 interaction.