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PDBsum entry 5dkr
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Metal binding protein/inhibitor
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PDB id
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5dkr
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PDB id:
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| Name: |
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Metal binding protein/inhibitor
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Title:
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Crystal structure of calcium-loaded s100b bound to sbi29
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Structure:
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Protein s100-b. Chain: a, b. Synonym: s-100 protein beta chain,s-100 protein subunit beta,s100 calcium-binding protein b. Engineered: yes
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Source:
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Bos taurus. Bovine. Organism_taxid: 9913. Gene: s100b. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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1.74Å
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R-factor:
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0.209
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R-free:
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0.247
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Authors:
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M.C.Cavalier,M.I.Ansari,A.D.Pierce,P.T.Wilder,L.E.Mcknight,E.P.Raman, D.B.Neau,P.Bezawada,M.J.Alasady,K.M.Varney,E.A.Toth,A.D.Mackerell Jr.,A.Coop,D.J.Weber
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Key ref:
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M.C.Cavalier
et al.
(2016).
Small Molecule Inhibitors of Ca(2+)-S100B Reveal Two Protein Conformations.
J Med Chem,
59,
592-608.
PubMed id:
DOI:
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Date:
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03-Sep-15
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Release date:
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20-Jan-16
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PROCHECK
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Headers
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References
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P02638
(S100B_BOVIN) -
Protein S100-B from Bos taurus
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Seq:
Struc:
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92 a.a.
89 a.a.
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Key: |
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Secondary structure |
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CATH domain |
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DOI no:
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J Med Chem
59:592-608
(2016)
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PubMed id:
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Small Molecule Inhibitors of Ca(2+)-S100B Reveal Two Protein Conformations.
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M.C.Cavalier,
M.I.Ansari,
A.D.Pierce,
P.T.Wilder,
L.E.McKnight,
E.P.Raman,
D.B.Neau,
P.Bezawada,
M.J.Alasady,
T.H.Charpentier,
K.M.Varney,
E.A.Toth,
A.D.MacKerell,
A.Coop,
D.J.Weber.
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ABSTRACT
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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.
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Links
