Divalent metal ion complexes of S100B in the absence and presence of pentamidine.

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TitleDivalent metal ion complexes of S100B in the absence and presence of pentamidine.
Publication TypeJournal Article
Year of Publication2008
AuthorsCharpentier, TH, Wilder, PT, Liriano, MA, Varney, KM, Pozharski, E, Mackerell, AD, Coop, A, Toth, EA, Weber, DJ
JournalJ Mol Biol
Volume382
Issue1
Pagination56-73
Date Published2008 Sep 26
ISSN1089-8638
KeywordsAnimals, Calcium, Cattle, Crystallography, X-Ray, Kinetics, Magnetic Resonance Spectroscopy, Models, Molecular, Nerve Growth Factors, Pentamidine, Protein Structure, Secondary, Rats, S100 Calcium Binding Protein beta Subunit, S100 Proteins, Thermodynamics, Zinc
Abstract

As part of an effort to inhibit S100B, structures of pentamidine (Pnt) bound to Ca(2+)-loaded and Zn(2+),Ca(2+)-loaded S100B were determined by X-ray crystallography at 2.15 A (R(free)=0.266) and 1.85 A (R(free)=0.243) resolution, respectively. These data were compared to X-ray structures solved in the absence of Pnt, including Ca(2+)-loaded S100B and Zn(2+),Ca(2+)-loaded S100B determined here (1.88 A; R(free)=0.267). In the presence and absence of Zn(2+), electron density corresponding to two Pnt molecules per S100B subunit was mapped for both drug-bound structures. One Pnt binding site (site 1) was adjacent to a p53 peptide binding site on S100B (+/-Zn(2+)), and the second Pnt molecule was mapped to the dimer interface (site 2; +/-Zn(2+)) and in a pocket near residues that define the Zn(2+) binding site on S100B. In addition, a conformational change in S100B was observed upon the addition of Zn(2+) to Ca(2+)-S100B, which changed the conformation and orientation of Pnt bound to sites 1 and 2 of Pnt-Zn(2+),Ca(2+)-S100B when compared to Pnt-Ca(2+)-S100B. That Pnt can adapt to this Zn(2+)-dependent conformational change was unexpected and provides a new mode for S100B inhibition by this drug. These data will be useful for developing novel inhibitors of both Ca(2+)- and Ca(2+),Zn(2+)-bound S100B.

DOI10.1016/j.jmb.2008.06.047
Alternate JournalJ. Mol. Biol.
PubMed ID18602402
PubMed Central IDPMC2636698
Grant ListS10 RR023447 / RR / NCRR NIH HHS / United States
K02 DA019634 / DA / NIDA NIH HHS / United States
K02 DA019634-01 / DA / NIDA NIH HHS / United States
S10 RR023447-01 / RR / NCRR NIH HHS / United States
S10 RR016812 / RR / NCRR NIH HHS / United States
R01 CA107331-01A3 / CA / NCI NIH HHS / United States
R01 CA107331-03 / CA / NCI NIH HHS / United States
R01 CA107331 / CA / NCI NIH HHS / United States
S10 RR016812-01 / RR / NCRR NIH HHS / United States
GM58888 / GM / NIGMS NIH HHS / United States
R01 CA107331-02 / CA / NCI NIH HHS / United States
CA107331 / CA / NCI NIH HHS / United States
S10 RR015741-01 / RR / NCRR NIH HHS / United States
R01 GM058888-10 / GM / NIGMS NIH HHS / United States
S10 RR015741 / RR / NCRR NIH HHS / United States
R01 GM058888-09 / GM / NIGMS NIH HHS / United States
R01 GM058888 / GM / NIGMS NIH HHS / United States