3OEV

Structure of yeast 20S open-gate proteasome with Compound 25


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.85 Å
  • R-Value Free: 0.257 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.220 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Optimization of a series of dipeptides with a P3 threonine residue as non-covalent inhibitors of the chymotrypsin-like activity of the human 20S proteasome.

Blackburn, C.Barrett, C.Blank, J.L.Bruzzese, F.J.Bump, N.Dick, L.R.Fleming, P.Garcia, K.Hales, P.Hu, Z.Jones, M.Liu, J.X.Sappal, D.S.Sintchak, M.D.Tsu, C.Gigstad, K.M.

(2010) Bioorg Med Chem Lett 20: 6581-6586

  • DOI: https://doi.org/10.1016/j.bmcl.2010.09.032
  • Primary Citation of Related Structures:  
    3OEU, 3OEV, 3SDI, 3SDK

  • PubMed Abstract: 

    Starting from a tripeptide screening hit, a series of dipeptide inhibitors of the proteasome with Thr as the P3 residue has been optimized with the aid of crystal structures in complex with the β-5/6 active site of y20S. Derivative 25, (β5 IC(50)=7.4 nM) inhibits only the chymotryptic activity of the proteasome, shows cellular activity against targets in the UPS, and inhibits proliferation.


  • Organizational Affiliation

    Millennium Pharmaceuticals Inc., 40 Landsdowne St., Cambridge, MA 02139, United States.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component Y7
A, O
250Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component Y13
B, P
235Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component PRE6
C, Q
241Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component PUP2
D, R
260Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 5
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component PRE5
E, S
233Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 6
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component C1
F, T
242Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 7
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component C7-alpha
G, U
243Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 8
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component PUP1
H, V
222Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 9
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component PUP3
I, W
204Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 10
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component C11
J, X
198Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 11
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component PRE2
K, Y
212Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 12
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component C5
L, Z
222Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 13
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component PRE4AA [auth 1],
M
233Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 14
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component PRE3BA [auth 2],
N
196Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3OE
Query on 3OE

Download Ideal Coordinates CCD File 
JA [auth K],
OA [auth Y]
4-(benzyloxy)-N-[(2S,3R)-3-hydroxy-1-{[(2S)-1-{[(3-methylthiophen-2-yl)methyl]amino}-1-oxo-4-phenylbutan-2-yl]amino}-1-oxobutan-2-yl]benzamide
C34 H37 N3 O5 S
ARBUDFCHDYTBDG-AVKNQKEWSA-N
MES
Query on MES

Download Ideal Coordinates CCD File 
KA [auth K],
PA [auth Y]
2-(N-MORPHOLINO)-ETHANESULFONIC ACID
C6 H13 N O4 S
SXGZJKUKBWWHRA-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
CA [auth F]
DA [auth F]
EA [auth G]
FA [auth H]
GA [auth I]
CA [auth F],
DA [auth F],
EA [auth G],
FA [auth H],
GA [auth I],
HA [auth I],
IA [auth K],
LA [auth L],
MA [auth L],
NA [auth N]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
3OE PDBBind:  3OEV IC50: 7.4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.85 Å
  • R-Value Free: 0.257 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.220 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 136.067α = 90
b = 299.946β = 113.17
c = 145.621γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-07-20
    Type: Initial release
  • Version 1.1: 2012-12-12
    Changes: Other
  • Version 1.2: 2024-02-21
    Changes: Data collection, Database references, Derived calculations