5L6B

Yeast 20S proteasome with mouse beta5i (1-138) and mouse beta6 (97-111; 118-133) in complex with ONX 0914


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.197 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

A humanized yeast proteasome identifies unique binding modes of inhibitors for the immunosubunit beta 5i.

Huber, E.M.Heinemeyer, W.de Bruin, G.Overkleeft, H.S.Groll, M.

(2016) EMBO J 35: 2602-2613

  • DOI: https://doi.org/10.15252/embj.201695222
  • Primary Citation of Related Structures:  
    5L52, 5L54, 5L55, 5L5A, 5L5B, 5L5D, 5L5E, 5L5F, 5L5H, 5L5I, 5L5J, 5L5O, 5L5P, 5L5Q, 5L5R, 5L5S, 5L5T, 5L5U, 5L5V, 5L5W, 5L5X, 5L5Y, 5L5Z, 5L60, 5L61, 5L62, 5L63, 5L64, 5L65, 5L66, 5L67, 5L68, 5L69, 5L6A, 5L6B, 5L6C, 5LTT

  • PubMed Abstract: 

    Inhibition of the immunoproteasome subunit β5i alleviates autoimmune diseases in preclinical studies and represents a promising new anti-inflammatory therapy. However, the lack of structural data on the human immunoproteasome still hampers drug design. Here, we systematically determined the potency of seven α' β' epoxyketone inhibitors with varying N-caps and P3-stereochemistry for mouse/human β5c/β5i and found pronounced differences in their subunit and species selectivity. Using X-ray crystallography, the compounds were analyzed for their modes of binding to chimeric yeast proteasomes that incorporate key parts of human β5c, human β5i or mouse β5i and the neighboring β6 subunit. The structural data reveal exceptional conformations for the most selective human β5i inhibitors and highlight subtle structural differences as the major reason for the observed species selectivity. Altogether, the presented results validate the humanized yeast proteasome as a powerful tool for structure-based development of β5i inhibitors with potential clinical applications.


  • Organizational Affiliation

    Center for Integrated Protein Science at the Department Chemie, Lehrstuhl für Biochemie Technische Universität München, Garching, Germany.


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
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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
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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
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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
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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
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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
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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
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Entity ID: 11
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-8,Proteasome subunit beta type-5
K, Y
211Mus musculusSaccharomyces cerevisiae S288C
This entity is chimeric
Mutation(s): 0 
Gene Names: Psmb8Lmp7Mc13PRE2DOA3PRG1YPR103WP8283.10
EC: 3.4.25.1
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Entity ID: 12
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-6,Proteasome subunit beta type-1,Proteasome subunit beta type-6,Proteasome subunit beta type-1,Proteasome subunit beta type-6
L, Z
222Saccharomyces cerevisiae S288CMus musculusMutation(s): 0 
Gene Names: PRE7PRS3PTS1YBL041WYBL0407Psmb1
EC: 3.4.25.1
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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
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Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
04C
Query on 04C

Download Ideal Coordinates CCD File 
EA [auth H]
JA [auth K]
NA [auth N]
QA [auth V]
SA [auth Y]
EA [auth H],
JA [auth K],
NA [auth N],
QA [auth V],
SA [auth Y],
VA [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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FA [auth H],
LA [auth K],
RA [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 J]
KA [auth K]
CA [auth G],
GA [auth I],
HA [auth I],
IA [auth J],
KA [auth K],
MA [auth L],
OA [auth N],
UA [auth Z]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.197 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 135.19α = 90
b = 300.84β = 112.94
c = 145.39γ = 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

Revision History  (Full details and data files)

  • Version 1.0: 2016-11-09
    Type: Initial release
  • Version 1.1: 2016-12-14
    Changes: Database references
  • Version 1.2: 2016-12-21
    Changes: Non-polymer description
  • Version 1.3: 2024-01-10
    Changes: Author supporting evidence, Data collection, Database references, Derived calculations, Refinement description