4QLS

yCP in complex with tripeptidic epoxyketone inhibitor 11


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.199 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.180 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Structure-based design of beta 1i or beta 5i specific inhibitors of human immunoproteasomes

De Bruin, G.Huber, E.M.Xin, B.T.Van Rooden, E.J.Al-Ayed, K.Kim, K.B.Kisselev, A.F.Driessen, C.Van der Stelt, M.Van der Marel, G.A.Groll, M.Overkleeft, H.S.

(2014) J Med Chem 57: 6197-6209

  • DOI: https://doi.org/10.1021/jm500716s
  • Primary Citation of Related Structures:  
    4QLQ, 4QLS, 4QLT, 4QLU, 4QLV

  • PubMed Abstract: 

    Mammalian genomes encode seven catalytic proteasome subunits, namely, β1c, β2c, β5c (assembled into constitutive 20S proteasome core particles), β1i, β2i, β5i (incorporated into immunoproteasomes), and the thymoproteasome-specific subunit β5t. Extensive research in the past decades has yielded numerous potent proteasome inhibitors including compounds currently used in the clinic to treat multiple myeloma and mantle cell lymphoma. Proteasome inhibitors that selectively target combinations of β1c/β1i, β2c/β2i, or β5c/β5i are available, yet ligands truly selective for a single proteasome activity are scarce. In this work we report the development of cell-permeable β1i and β5i selective inhibitors that outperform existing leads in terms of selectivity and/or potency. These compounds are the result of a rational design strategy using known inhibitors as starting points and introducing structural features according to the X-ray structures of the murine constitutive and immunoproteasome 20S core particles.


  • Organizational Affiliation

    Gorlaeus Laboratories, Leiden Institute of Chemistry and Netherlands Proteomics Centre , Einsteinweg 55, 2333 CC Leiden, The Netherlands.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-2
A, O
250Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
Find proteins for P23639 (Saccharomyces cerevisiae (strain ATCC 204508 / S288c))
Explore P23639 
Go to UniProtKB:  P23639
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP23639
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-3
B, P
258Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
Find proteins for P23638 (Saccharomyces cerevisiae (strain ATCC 204508 / S288c))
Explore P23638 
Go to UniProtKB:  P23638
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP23638
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-4
C, Q
254Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
Find proteins for P40303 (Saccharomyces cerevisiae (strain ATCC 204508 / S288c))
Explore P40303 
Go to UniProtKB:  P40303
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP40303
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-5
D, R
260Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
Find proteins for P32379 (Saccharomyces cerevisiae (strain ATCC 204508 / S288c))
Explore P32379 
Go to UniProtKB:  P32379
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP32379
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 5
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-6
E, S
234Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
Find proteins for P40302 (Saccharomyces cerevisiae (strain ATCC 204508 / S288c))
Explore P40302 
Go to UniProtKB:  P40302
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP40302
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
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
Find proteins for P21242 (Saccharomyces cerevisiae (strain ATCC 204508 / S288c))
Explore P21242 
Go to UniProtKB:  P21242
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP21242
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 7
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-1
G, U
252Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
Find proteins for P21243 (Saccharomyces cerevisiae (strain ATCC 204508 / S288c))
Explore P21243 
Go to UniProtKB:  P21243
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP21243
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 8
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-2
H, V
232Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
Find proteins for P25043 (Saccharomyces cerevisiae (strain ATCC 204508 / S288c))
Explore P25043 
Go to UniProtKB:  P25043
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP25043
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 9
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-3
I, W
205Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
Find proteins for P25451 (Saccharomyces cerevisiae (strain ATCC 204508 / S288c))
Explore P25451 
Go to UniProtKB:  P25451
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP25451
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 10
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-4
J, X
198Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
Find proteins for P22141 (Saccharomyces cerevisiae (strain ATCC 204508 / S288c))
Explore P22141 
Go to UniProtKB:  P22141
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP22141
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 11
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-5
K, Y
212Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
Find proteins for P30656 (Saccharomyces cerevisiae (strain ATCC 204508 / S288c))
Explore P30656 
Go to UniProtKB:  P30656
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP30656
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 12
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-6
L, Z
222Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
Find proteins for P23724 (Saccharomyces cerevisiae (strain ATCC 204508 / S288c))
Explore P23724 
Go to UniProtKB:  P23724
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP23724
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 13
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-7AA [auth a],
M
246Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
UniProt
Find proteins for P30657 (Saccharomyces cerevisiae (strain ATCC 204508 / S288c))
Explore P30657 
Go to UniProtKB:  P30657
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP30657
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
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
Find proteins for P38624 (Saccharomyces cerevisiae (strain ATCC 204508 / S288c))
Explore P38624 
Go to UniProtKB:  P38624
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP38624
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
37Y
Query on 37Y

Download Ideal Coordinates CCD File 
GA [auth K],
MA [auth Y]
N-(morpholin-4-ylacetyl)-D-alanyl-N-[(2S,4R)-1-cyclohexyl-5-hydroxy-4-methyl-3-oxopentan-2-yl]-O-methyl-L-tyrosinamide
C31 H48 N4 O7
CTVSVADXPCPAKI-SZUBIPLGSA-N
MES
Query on MES

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

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.199 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.180 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 136.42α = 90
b = 299.95β = 113.18
c = 145.96γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XSCALEdata scaling
REFMACphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-07-23
    Type: Initial release
  • Version 1.1: 2014-10-01
    Changes: Database references
  • Version 1.2: 2020-08-12
    Changes: Derived calculations, Structure summary
  • Version 1.3: 2020-08-19
    Changes: Structure summary
  • Version 1.4: 2023-11-08
    Changes: Data collection, Database references, Refinement description