4NO9

yCP in complex with Z-Leu-Leu-Leu-epoxyketone


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.203 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.179 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Systematic Comparison of Peptidic Proteasome Inhibitors Highlights the alpha-Ketoamide Electrophile as an Auspicious Reversible Lead Motif.

Stein, M.L.Cui, H.Beck, P.Dubiella, C.Voss, C.Kruger, A.Schmidt, B.Groll, M.

(2014) Angew Chem Int Ed Engl 53: 1679-1683

  • DOI: https://doi.org/10.1002/anie.201308984
  • Primary Citation of Related Structures:  
    4NNN, 4NNW, 4NO1, 4NO6, 4NO8, 4NO9

  • PubMed Abstract: 

    The ubiquitin-proteasome system (UPS) has been successfully targeted by both academia and the pharmaceutical industry for oncological and immunological applications. Typical proteasome inhibitors are based on a peptidic backbone endowed with an electrophilic C-terminus by which they react with the active proteolytic sites. Although the peptide moiety has attracted much attention in terms of subunit selectivity, the target specificity and biological stability of the compounds are largely determined by the reactive warheads. In this study, we have carried out a systematic investigation of described electrophiles by a combination of in vitro, in vivo, and structural methods in order to disclose the implications of altered functionality and chemical reactivity. Thereby, we were able to introduce and characterize the class of α-ketoamides as the most potent reversible inhibitors with possible applications for the therapy of solid tumors as well as autoimmune disorders.


  • Organizational Affiliation

    Center for Integrated Protein Science at the Department Chemie, Lehrstuhl für Biochemie, TU München (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
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
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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
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
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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 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
2L0
Query on 2L0

Download Ideal Coordinates CCD File 
DA [auth H],
GA [auth K],
LA [auth Y]
N-[(benzyloxy)carbonyl]-L-leucyl-N-[(2R,3S,4S)-1,3-dihydroxy-2,6-dimethylheptan-4-yl]-L-leucinamide
C29 H49 N3 O6
BQCZUBTUMXOONX-KAPZOZIZSA-N
2LR
Query on 2LR

Download Ideal Coordinates CCD File 
JA [auth V]N-[(benzyloxy)carbonyl]-L-leucyl-N-{(1R,2S)-1-hydroxy-4-methyl-1-[(2R)-2-methyloxiran-2-yl]pentan-2-yl}-L-leucinamide
C29 H47 N3 O6
HBAZSHAOSQCUFB-ABJYOQOBSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
CA [auth G]
EA [auth H]
FA [auth I]
HA [auth K]
IA [auth N]
CA [auth G],
EA [auth H],
FA [auth I],
HA [auth K],
IA [auth N],
KA [auth V],
MA [auth Y],
NA [auth Z]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.203 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.179 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 136.49α = 90
b = 301.49β = 114.15
c = 144.39γ = 90
Software Package:
Software NamePurpose
XDSdata scaling
REFMACrefinement
XDSdata reduction
XSCALEdata scaling
REFMACphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-02-12
    Type: Initial release
  • Version 1.1: 2014-02-19
    Changes: Database references
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description