3MG6

Structure of yeast 20S open-gate proteasome with Compound 6


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.249 
  • R-Value Work: 0.215 
  • R-Value Observed: 0.215 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Characterization of a new series of non-covalent proteasome inhibitors with exquisite potency and selectivity for the 20S beta5-subunit.

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

(2010) Biochem J 430: 461-476

  • DOI: https://doi.org/10.1042/BJ20100383
  • Primary Citation of Related Structures:  
    3MG0, 3MG4, 3MG6, 3MG7, 3MG8

  • PubMed Abstract: 

    The mammalian 26S proteasome is a 2500 kDa multi-catalytic complex involved in intracellular protein degradation. We describe the synthesis and properties of a novel series of non-covalent di-peptide inhibitors of the proteasome based [corrected] on a capped tri-peptide that was first identified by high-throughput screening of a library of approx. 350000 compounds for inhibitors of the ubiquitin-proteasome system in cells. We show that these compounds are entirely selective for the beta5 (chymotrypsin-like) site over the beta1 (caspase-like) and beta2 (trypsin-like) sites of the 20S core particle of the proteasome, and over a panel of less closely related proteases. Compound optimization, guided by X-ray crystallography of the liganded 20S core particle, confirmed their non-covalent binding mode and provided a structural basis for their enhanced in vitro and cellular potencies. We demonstrate that such compounds show low nanomolar IC50 values for the human 20S beta5 site in vitro, and that pharmacological inhibition of this site in cells is sufficient to potently inhibit the degradation of a tetra-ubiquitin-luciferase reporter, activation of NFkappaB (nuclear factor kappaB) in response to TNF-alpha (tumour necrosis factor-alpha) and the proliferation of cancer cells. Finally, we identified capped di-peptides that show differential selectivity for the beta5 site of the constitutively expressed proteasome and immunoproteasome in vitro and in B-cell lymphomas. Collectively, these studies describe the synthesis, activity and binding mode of a new series of non-covalent proteasome inhibitors with unprecedented potency and selectivity for the beta5 site, and which can discriminate between the constitutive proteasome and immunoproteasome in vitro and in cells.


  • Organizational Affiliation

    Millennium Pharmaceuticals, Inc., Cambridge, MA 02139, USA.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component Y7
A, O
250Saccharomyces cerevisiaeMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component Y13
B, P
245Saccharomyces cerevisiaeMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component PRE6
C, Q
243Saccharomyces cerevisiaeMutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component PUP2
D, R
250Saccharomyces cerevisiaeMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 5
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component PRE5
E, S
234Saccharomyces cerevisiaeMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 6
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component C1
F, T
248Saccharomyces cerevisiaeMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 7
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component C7-alpha
G, U
252Saccharomyces cerevisiaeMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 8
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component PUP1
H, V
222Saccharomyces cerevisiaeMutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 9
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component PUP3
I, W
205Saccharomyces cerevisiaeMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 10
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component C11
J, X
198Saccharomyces cerevisiaeMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 11
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component PRE2
K, Y
212Saccharomyces cerevisiaeMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 12
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component C5
L, Z
241Saccharomyces cerevisiaeMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 13
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component PRE4AA [auth 1],
M
266Saccharomyces cerevisiaeMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 14
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component PRE3BA [auth 2],
N
196Saccharomyces cerevisiaeMutation(s): 0 
EC: 3.4.25.1
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Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
LZT
Query on LZT

Download Ideal Coordinates CCD File 
JA [auth K],
OA [auth Y]
N~2~-{[(1S)-6-methoxy-3-oxo-2,3-dihydro-1H-inden-1-yl]acetyl}-N-{(1S)-1-[(4-methylbenzyl)carbamoyl]-3-phenylpropyl}-L-threoninamide
C34 H39 N3 O6
XTNVDVZDMWYKHD-TWQSKLGKSA-N
MES
Query on MES

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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
LZT PDBBind:  3MG6 Ki: 13 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.249 
  • R-Value Work: 0.215 
  • R-Value Observed: 0.215 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 137.253α = 90
b = 299.646β = 113.67
c = 145.785γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
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: 2011-05-18
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-11-08
    Changes: Refinement description
  • Version 1.3: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description