4LTC

Crystal structure of yeast 20S proteasome in complex with enone carmaphycin analogue 6


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.233 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.205 

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Ligand Structure Quality Assessment 


This is version 1.0 of the entry. See complete history


Literature

Enzyme inhibition by hydroamination: design and mechanism of a hybrid carmaphycin-syringolin enone proteasome inhibitor.

Trivella, D.B.Pereira, A.R.Stein, M.L.Kasai, Y.Byrum, T.Valeriote, F.A.Tantillo, D.J.Groll, M.Gerwick, W.H.Moore, B.S.

(2014) Chem Biol 21: 782-791

  • DOI: https://doi.org/10.1016/j.chembiol.2014.04.010
  • Primary Citation of Related Structures:  
    4HNP, 4HRC, 4HRD, 4LTC

  • PubMed Abstract: 

    Hydroamination reactions involving the addition of an amine to an inactivated alkene are entropically prohibited and require strong chemical catalysts. While this synthetic process is efficient at generating substituted amines, there is no equivalent in small molecule-mediated enzyme inhibition. We report an unusual mechanism of proteasome inhibition that involves a hydroamination reaction of alkene derivatives of the epoxyketone natural product carmaphycin. We show that the carmaphycin enone first forms a hemiketal intermediate with the catalytic Thr1 residue of the proteasome before cyclization by an unanticipated intramolecular alkene hydroamination reaction, resulting in a stable six-membered morpholine ring. The carmaphycin enone electrophile, which does not undergo a 1,4-Michael addition as previously observed with vinyl sulfone and α,β-unsaturated amide-based inhibitors, is partially reversible and gives insight into the design of proteasome inhibitors for cancer chemotherapy.


  • Organizational Affiliation

    Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, La Jolla, CA 92093-0212, USA; Institute of Chemistry, University of Campinas, Campinas SP 13083-970, Brazil; Brazilian Biosciences National Laboratory, National Center for Research in Energy and Materials, Campinas SP 13083-970, Brazil.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-2A,
H [auth O]
250Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-3B,
I [auth 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-4C,
J [auth Q]
254Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-5D,
K [auth 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-6E,
L [auth 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-7F,
M [auth T]
287Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 7
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-1G,
N [auth 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-2O [auth H],
V
232Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 9
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-3P [auth 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-4Q [auth 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-5R [auth K],
Y
212Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Entity ID: 12
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-6S [auth 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],
T [auth M]
233Saccharomyces 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],
U [auth N]
196Saccharomyces cerevisiae S288CMutation(s): 0 
EC: 3.4.25.1
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Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
EC6
Query on EC6

Download Ideal Coordinates CCD File 
CA [auth K],
DA [auth Y]
N-hexanoyl-L-valyl-N~1~-[(4S,5S,6R)-5-hydroxy-2,6-dimethyloctan-4-yl]-N~5~,N~5~-dimethyl-L-glutamamide
C28 H54 N4 O5
BFKSFYOCNVYLSG-DGTHGUPJSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.233 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.205 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 135.17α = 90
b = 300.23β = 112.79
c = 144.38γ = 90
Software Package:
Software NamePurpose
XSCALEdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
CNSphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-07-02
    Type: Initial release