4EU2

Crystal structure of 20s proteasome with novel inhibitor K-7174


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.51 Å
  • R-Value Free: 0.255 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.205 

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Literature

Homopiperazine derivatives as a novel class of proteasome inhibitors with a unique mode of proteasome binding.

Kikuchi, J.Shibayama, N.Yamada, S.Wada, T.Nobuyoshi, M.Izumi, T.Akutsu, M.Kano, Y.Sugiyama, K.Ohki, M.Park, S.Y.Furukawa, Y.

(2013) PLoS One 8: e60649-e60649

  • DOI: https://doi.org/10.1371/journal.pone.0060649
  • Primary Citation of Related Structures:  
    4EU2

  • PubMed Abstract: 

    The proteasome is a proteolytic machinery that executes the degradation of polyubiquitinated proteins to maintain cellular homeostasis. Proteasome inhibition is a unique and effective way to kill cancer cells because they are sensitive to proteotoxic stress. Indeed, the proteasome inhibitor bortezomib is now indispensable for the treatment of multiple myeloma and other intractable malignancies, but is associated with patient inconvenience due to intravenous injection and emerging drug resistance. To resolve these problems, we attempted to develop orally bioavailable proteasome inhibitors with distinct mechanisms of action and identified homopiperazine derivatives (HPDs) as promising candidates. Biochemical and crystallographic studies revealed that some HPDs inhibit all three catalytic subunits (ß 1, ß 2 and ß 5) of the proteasome by direct binding, whereas bortezomib and other proteasome inhibitors mainly act on the ß5 subunit. Proteasome-inhibitory HPDs exhibited cytotoxic effects on cell lines from various hematological malignancies including myeloma. Furthermore, K-7174, one of the HPDs, was able to inhibit the growth of bortezomib-resistant myeloma cells carrying a ß5-subunit mutation. Finally, K-7174 had additive effects with bortezomib on proteasome inhibition and apoptosis induction in myeloma cells. Taken together, HPDs could be a new class of proteasome inhibitors, which compensate for the weak points of conventional ones and overcome the resistance to bortezomib.


  • Organizational Affiliation

    Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component C7-alpha
A, O
241Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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UniProt GroupP21243
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component Y7
B, P
250Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component Y13
C, Q
244Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component PRE6
D, R
241Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 5
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component PUP2
E, S
242Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 6
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component PRE5
F, T
233Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 7
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component C1
G, U
244Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 8
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component PRE3
H, V
196Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 9
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component PUP1
I, W
222Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 10
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component PUP3
J, X
204Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 11
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component C11
K, Y
198Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 12
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component PRE2
L, Z
212Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 13
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component C5AA [auth 1],
M
222Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 14
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome component PRE4BA [auth 2],
N
233Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.51 Å
  • R-Value Free: 0.255 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.205 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 134.264α = 90
b = 301.363β = 112.86
c = 143.964γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
HKL-2000data collection
HKL-2000data reduction
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-05-01
    Type: Initial release
  • Version 1.1: 2024-03-20
    Changes: Data collection, Database references, Derived calculations