5ER5

Crystal Structure of Calcium-loaded S100B bound to SC1990

Summary for 5ER5

• Entry DOI: 10.2210/pdb5er5/pdb
• Related: 4PEZ 5DKR 5ER4
• Descriptor: Protein S100-B, CALCIUM ION, ETHIDIUM, ... (4 entities in total)
• Functional Keywords: malignant melanoma, calcium binding, complex, covalent inhibitor, metal binding protein-inhibitor complex, metal binding protein/inhibitor
• Biological source: Bos taurus (Bovine)
• Total number of polymer chains: 1
• Total formula weight: 11076.53

Authors

Cavalier, M.C.,Melville, Z.E.,Aligholizadeh, E.,Fang, L.,Alasady, M.J.,Pierce, A.D.,Wilder, P.T.,MacKerell Jr., A.D.,Weber, D.J. (deposition date: 2015-11-13, release date: 2016-06-08, Last modification date: 2023-09-27)

Primary citation

Cavalier, M.C.,Melville, Z.,Aligholizadeh, E.,Raman, E.P.,Yu, W.,Fang, L.,Alasady, M.,Pierce, A.D.,Wilder, P.T.,MacKerell, A.D.,Weber, D.J.
Novel protein-inhibitor interactions in site 3 of Ca(2+)-bound S100B as discovered by X-ray crystallography.
Acta Crystallogr D Struct Biol, 72:753-760, 2016

PubMed Abstract: Structure-based drug discovery is under way to identify and develop small-molecule S100B inhibitors (SBiXs). Such inhibitors have therapeutic potential for treating malignant melanoma, since high levels of S100B downregulate wild-type p53 tumor suppressor function in this cancer. Computational and X-ray crystallographic studies of two S100B-SBiX complexes are described, and both compounds (apomorphine hydrochloride and ethidium bromide) occupy an area of the S100B hydrophobic cleft which is termed site 3. These data also reveal novel protein-inhibitor interactions which can be used in future drug-design studies to improve SBiX affinity and specificity. Of particular interest, apomorphine hydrochloride showed S100B-dependent killing in melanoma cell assays, although the efficacy exceeds its affinity for S100B and implicates possible off-target contributions. Because there are no structural data available for compounds occupying site 3 alone, these studies contribute towards the structure-based approach to targeting S100B by including interactions with residues in site 3 of S100B.

PubMed: 27303795
DOI: 10.1107/S2059798316005532

Experimental method

X-RAY DIFFRACTION (1.26 Å)