3gk4
X-ray structure of bovine SBi523,Ca(2+)-S100B
Structural highlights
FunctionS100B_BOVIN Weakly binds calcium but binds zinc very tightly-distinct binding sites with different affinities exist for both ions on each monomer. Physiological concentrations of potassium ion antagonize the binding of both divalent cations, especially affecting high-affinity calcium-binding sites. Binds to and initiates the activation of STK38 by releasing autoinhibitory intramolecular interactions within the kinase. Interaction with AGER after myocardial infarction may play a role in myocyte apoptosis by activating ERK1/2 and p53/TP53 signaling. Could assist ATAD3A cytoplasmic processing, preventing aggregation and favoring mitochondrial localization (By similarity).[1] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedStructural studies are part of a rational drug design program underway to inhibit the S100B-p53 interaction and restore wild-type p53 function in malignant melanoma. To this end, structures of three compounds (SBi132, SBi1279, and SBi523) bound to Ca<sup>2+</sup>-S100B were determined by X-ray crystallography at 2.10 A (Rfree = 0.257), 1.98 A (Rfree = 0.281) and 1.90 A (Rfree = 0.228) resolution, respectively. Upon comparison, SBi132, SBi279, and SBi523 were found to bind in distinct locations/orientations within the hydrophobic target binding pocket of Ca<sup>2+</sup>-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, 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<sup>2+</sup>-S100B overlaps the SBi132 and SBi523 sites and contacts residues in both loop 2 (Ser-41, His-42, Phe-43, Leu-44, Glu-45) and helix 4 (Ile-80, Ala-83, Cys-84, Phe-87 and Phe-88). NMR data, including saturation transfer difference (STD) and <sup>15</sup>N backbone and <sup>13</sup>C sidechain 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<sup>2+</sup>-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 by yielding novel tight binding inhibitors specific for blocking protein-protein interactions involving S100B. Small molecules bound to unique sites in the target protein binding cleft of calcium-bound S100B as characterized by nuclear magnetic resonance (NMR) 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. 2009 May 26. PMID:19469484[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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