5DKN

Crystal Structure of Calcium-loaded S100B bound to SBi4225

Summary for 5DKN

• Entry DOI: 10.2210/pdb5dkn/pdb
• Related: 5DKQ 5DKR
• Descriptor: Protein S100-B, CALCIUM ION, 2,2'-[heptane-1,7-diylbis(oxybenzene-4,1-diyl)]bis(1H-imidazole), ... (4 entities in total)
• Functional Keywords: malignant melanoma, calcium binding, 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: 11178.65

Authors

Cavalier, M.C.,Ansari, M.I.,Pierce, A.D.,Wilder, P.T.,McKnight, L.E.,Raman, E.P.,Neau, D.B.,Bezawada, P.,Alasady, M.J.,Varney, K.M.,Toth, E.A.,MacKerell Jr., A.D.,Coop, A.,Weber, D.J. (deposition date: 2015-09-03, release date: 2016-01-20, Last modification date: 2023-09-27)

Primary citation

Cavalier, M.C.,Ansari, M.I.,Pierce, A.D.,Wilder, P.T.,McKnight, L.E.,Raman, E.P.,Neau, D.B.,Bezawada, P.,Alasady, M.J.,Charpentier, T.H.,Varney, K.M.,Toth, E.A.,MacKerell, A.D.,Coop, A.,Weber, D.J.
Small Molecule Inhibitors of Ca(2+)-S100B Reveal Two Protein Conformations.
J.Med.Chem., 59:592-608, 2016

PubMed Abstract: The drug pentamidine inhibits calcium-dependent complex formation with p53 ((Ca)S100B·p53) in malignant melanoma (MM) and restores p53 tumor suppressor activity in vivo. However, off-target effects associated with this drug were problematic in MM patients. Structure-activity relationship (SAR) studies were therefore completed here with 23 pentamidine analogues, and X-ray structures of (Ca)S100B·inhibitor complexes revealed that the C-terminus of S100B adopts two different conformations, with location of Phe87 and Phe88 being the distinguishing feature and termed the "FF-gate". For symmetric pentamidine analogues ((Ca)S100B·5a, (Ca)S100B·6b) a channel between sites 1 and 2 on S100B was occluded by residue Phe88, but for an asymmetric pentamidine analogue ((Ca)S100B·17), this same channel was open. The (Ca)S100B·17 structure illustrates, for the first time, a pentamidine analog capable of binding the "open" form of the "FF-gate" and provides a means to block all three "hot spots" on (Ca)S100B, which will impact next generation (Ca)S100B·p53 inhibitor design.

PubMed: 26727270
DOI: 10.1021/acs.jmedchem.5b01369

Experimental method

X-RAY DIFFRACTION (1.528 Å)