5DKR

Crystal Structure of Calcium-loaded S100B bound to SBi29


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.74 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.205 
  • R-Value Observed: 0.209 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Small Molecule Inhibitors of Ca(2+)-S100B Reveal Two Protein Conformations.

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.

(2016) J Med Chem 59: 592-608

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b01369
  • Primary Citation of Related Structures:  
    5DKN, 5DKQ, 5DKR

  • 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.


  • Organizational Affiliation

    Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics (CBT), University of Maryland School of Medicine , Baltimore, Maryland 21201, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Protein S100-B
A, B
92Bos taurusMutation(s): 0 
Gene Names: S100B
UniProt
Find proteins for P02638 (Bos taurus)
Explore P02638 
Go to UniProtKB:  P02638
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP02638
Sequence Annotations
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  • Reference Sequence
Small Molecules
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.74 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.205 
  • R-Value Observed: 0.209 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 46.745α = 90
b = 47.443β = 90
c = 90.343γ = 90
Software Package:
Software NamePurpose
Aimlessdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
PHENIXphasing
XDSdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Cancer Institute (NIH/NCI)United StatesCA154274
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesGM58888
National Institutes of Health/National Cancer Institute (NIH/NCI)United StatesCA107331

Revision History  (Full details and data files)

  • Version 1.0: 2016-01-20
    Type: Initial release
  • Version 1.1: 2016-02-10
    Changes: Database references
  • Version 1.2: 2017-09-27
    Changes: Author supporting evidence, Database references, Derived calculations, Refinement description
  • Version 1.3: 2019-12-04
    Changes: Author supporting evidence
  • Version 1.4: 2023-09-27
    Changes: Data collection, Database references, Derived calculations, Refinement description