6H39

Yeast 20S proteasome in complex with the peptidic non-covalent binding inhibitor RTS-V5


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.217 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.189 

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This is version 1.2 of the entry. See complete history


Literature

Discovery of the First-in-Class Dual Histone Deacetylase-Proteasome Inhibitor.

Bhatia, S.Krieger, V.Groll, M.Osko, J.D.Reßing, N.Ahlert, H.Borkhardt, A.Kurz, T.Christianson, D.W.Hauer, J.Hansen, F.K.

(2018) J Med Chem 61: 10299-10309

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b01487
  • Primary Citation of Related Structures:  
    6CW8, 6H39

  • PubMed Abstract: 

    Dual- or multitarget drugs have emerged as a promising alternative to combination therapies. Proteasome inhibitors (PIs) possess synergistic activity with histone deacetylase (HDAC) inhibitors due to the simultaneous blockage of the ubiquitin degradation and aggresome pathways. Here, we present the design, synthesis, binding modes, and anticancer properties of RTS-V5 as the first-in-class dual HDAC-proteasome ligand. The inhibition of both targets was confirmed by biochemical and cellular assays as well as X-ray crystal structures of the 20S proteasome and HDAC6 complexed with RTS-V5. Cytotoxicity assays with leukemia and multiple myeloma cell lines as well as therapy refractory primary patient-derived leukemia cells demonstrated that RTS-V5 possesses potent and selective anticancer activity. Our results will thus guide the structure-based optimization of dual HDAC-proteasome inhibitors for the treatment of hematological malignancies.


  • Organizational Affiliation

    Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty , Heinrich Heine University Düsseldorf , Moorenstrasse 5 , 40225 Düsseldorf , 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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UniProt GroupP23639
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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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UniProt GroupP23638
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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
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
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Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FGY
Query on FGY

Download Ideal Coordinates CCD File 
FA [auth K],
OA [auth Y]
N-(2,2-dimethylpropyl)-N~2~-[4-(hydroxycarbamoyl)benzene-1-carbonyl]-L-asparaginyl-N-benzyl-L-alaninamide
C27 H35 N5 O6
CMINWSPSBRREEO-UWJYYQICSA-N
MES
Query on MES

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IA [auth K],
RA [auth Y]
2-(N-MORPHOLINO)-ETHANESULFONIC ACID
C6 H13 N O4 S
SXGZJKUKBWWHRA-UHFFFAOYSA-N
SO4
Query on SO4

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KA [auth N],
TA [auth b]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
CL
Query on CL

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

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CA [auth G]
EA [auth I]
GA [auth K]
HA [auth K]
JA [auth N]
CA [auth G],
EA [auth I],
GA [auth K],
HA [auth K],
JA [auth N],
MA [auth V],
NA [auth X],
PA [auth Y],
QA [auth Y],
SA [auth Z]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.217 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.189 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 137.14α = 90
b = 300.78β = 113.48
c = 145.08γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
XSCALEdata scaling
REFMACphasing
REFMACrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
German Research FoundationGermanySFB1035/A2

Revision History  (Full details and data files)

  • Version 1.0: 2018-11-07
    Type: Initial release
  • Version 1.1: 2018-11-28
    Changes: Data collection, Database references
  • Version 1.2: 2024-01-17
    Changes: Data collection, Database references, Derived calculations, Refinement description