5CGI

Yeast 20S proteasome beta5-G48C mutant in complex with ONX 0914


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.187 

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Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Selective Inhibition of the Immunoproteasome by Structure-Based Targeting of a Non-catalytic Cysteine.

Dubiella, C.Baur, R.Cui, H.Huber, E.M.Groll, M.

(2015) Angew Chem Int Ed Engl 54: 15888-15891

  • DOI: https://doi.org/10.1002/anie.201506631
  • Primary Citation of Related Structures:  
    5CGF, 5CGG, 5CGH, 5CGI

  • PubMed Abstract: 

    Clinically applied proteasome inhibitors induce cell death by concomitant blockage of constitutive and immunoproteasomes. In contrast, selective immunoproteasome inhibition is less cytotoxic and has the potential to modulate chronic inflammation and autoimmune diseases. In this study, we rationally designed decarboxylated peptides that covalently target a non-catalytic cysteine of the immunoproteasome subunit β5i with α-chloroacetamide-containing sidechains. The enhanced isoform specificity decreased cytotoxic effects and the compound suppressed the production of inflammatory cytokines. Structure-based optimization led to over 150-fold selectivity for subunit β5i over β5c. This new compound class provides a promising starting point for the development of selective immunoproteasome inhibitors as potential anti-inflammatory agents.


  • Organizational Affiliation

    Center for Integrated Protein Science Munich (CIPSM), Department of Chemistry, Technische Universität München, Lichtenbergstrasse 4, 85748 Garching (Germany). christian.dubiella@mytum.de.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-2
A, O
250Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-3
B, P
258Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-4
C, Q
254Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-5
D, R
260Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 5
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-6
E, S
234Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 6
MoleculeChains Sequence LengthOrganismDetailsImage
Probable proteasome subunit alpha type-7
F, T
288Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 7
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-1
G, U
252Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 8
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-2
H, V
232Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 9
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-3
I, W
205Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 10
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-4
J, X
198Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 11
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-5
K, Y
212Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 12
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-6
L, Z
222Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
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Entity ID: 13
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-7AA [auth a],
M
246Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 14
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-1BA [auth b],
N
196Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
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Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
04C
Query on 04C

Download Ideal Coordinates CCD File 
FA [auth H]
LA [auth K]
OA [auth N]
RA [auth V]
VA [auth Y]
FA [auth H],
LA [auth K],
OA [auth N],
RA [auth V],
VA [auth Y],
XA [auth b]
1,2,4-trideoxy-4-methyl-2-{[N-(morpholin-4-ylacetyl)-L-alanyl-O-methyl-L-tyrosyl]amino}-1-phenyl-D-xylitol
C31 H44 N4 O7
SLVOSRJOLWNALP-QAKIEGLASA-N
MES
Query on MES

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EA [auth H],
KA [auth K],
QA [auth V],
TA [auth Y]
2-(N-MORPHOLINO)-ETHANESULFONIC ACID
C6 H13 N O4 S
SXGZJKUKBWWHRA-UHFFFAOYSA-N
CL
Query on CL

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DA [auth G],
PA [auth U]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
MG
Query on MG

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CA [auth G]
GA [auth I]
HA [auth I]
IA [auth K]
MA [auth L]
CA [auth G],
GA [auth I],
HA [auth I],
IA [auth K],
MA [auth L],
NA [auth N],
SA [auth X],
WA [auth Z]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
NA
Query on NA

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JA [auth K],
UA [auth Y]
SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.187 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 136.19α = 90
b = 300.03β = 112.96
c = 145.04γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XSCALEdata scaling
REFMACphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
German Research FoundationGermanyGR1861/10-1
German Research FoundationGermanySFB1035/A2

Revision History  (Full details and data files)

  • Version 1.0: 2015-11-25
    Type: Initial release
  • Version 1.1: 2016-01-27
    Changes: Database references
  • Version 1.2: 2016-02-03
    Changes: Refinement description, Structure summary
  • Version 1.3: 2017-03-29
    Changes: Database references
  • Version 1.4: 2018-06-13
    Changes: Author supporting evidence, Data collection, Structure summary
  • Version 1.5: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Refinement description