4R3O

Human Constitutive 20S Proteasome


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.206 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Crystal Structure of the Human 20S Proteasome in Complex with Carfilzomib.

Harshbarger, W.Miller, C.Diedrich, C.Sacchettini, J.

(2015) Structure 23: 418-424

  • DOI: https://doi.org/10.1016/j.str.2014.11.017
  • Primary Citation of Related Structures:  
    4R3O, 4R67

  • PubMed Abstract: 

    Proteasome inhibition is highly effective as a treatment for multiple myeloma, and recently carfilzomib was granted US FDA approval for the treatment of relapsed and refractory multiple myeloma. Here, we report the X-ray crystal structure of the human constitutive 20S proteasome with and without carfilzomib bound at 2.9 and 2.6 Å, respectively. Our data indicate that the S3 and S4 binding pockets play a pivotal role in carfilzomib's selectivity for chymotrypsin-like sites. Structural comparison with the mouse immunoproteasome crystal structure reveals amino acid substitutions that explain carfilzomib's slight preference for chymotrypsin-like subunits of constitutive proteasomes. In addition, comparison of the human proteasome:carfilzomib complex with the mouse proteasome:PR-957 complex reveals new details that explain why PR-957 is selective for immunoproteasomes. Together, the data presented here support the design of inhibitors for either constitutive or immunoproteasomes, with implications for the treatment of cancers as well as autoimmune and neurodegenerative diseases.


  • Organizational Affiliation

    Department of Chemistry, Texas A&M University, College Station, TX 77842-3012, USA.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-6
A, O
244Homo sapiensMutation(s): 0 
EC: 3.4.25.1
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GTEx:  ENSG00000100902 
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UniProt GroupP60900
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-2
B, P
233Homo sapiensMutation(s): 0 
EC: 3.4.25.1
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GTEx:  ENSG00000106588 
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UniProt GroupP25787
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-4
C, Q
250Homo sapiensMutation(s): 0 
EC: 3.4.25.1
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GTEx:  ENSG00000041357 
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UniProt GroupP25789
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-7
D, R
243Homo sapiensMutation(s): 0 
EC: 3.4.25.1
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GTEx:  ENSG00000101182 
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Entity ID: 5
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-5
E, S
234Homo sapiensMutation(s): 0 
EC: 3.4.25.1
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GTEx:  ENSG00000143106 
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Entity ID: 6
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-1
F, T
238Homo sapiensMutation(s): 0 
EC: 3.4.25.1
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GTEx:  ENSG00000129084 
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Entity ID: 7
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit alpha type-3
G, U
245Homo sapiensMutation(s): 0 
EC: 3.4.25.1
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GTEx:  ENSG00000100567 
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Entity ID: 8
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-6
H, V
202Homo sapiensMutation(s): 0 
EC: 3.4.25.1
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Find proteins for P28072 (Homo sapiens)
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GTEx:  ENSG00000142507 
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UniProt GroupP28072
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Entity ID: 9
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-7
I, W
220Homo sapiensMutation(s): 0 
EC: 3.4.25.1
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GTEx:  ENSG00000136930 
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UniProt GroupQ99436
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Entity ID: 10
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-3
J, X
204Homo sapiensMutation(s): 0 
EC: 3.4.25.1
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GTEx:  ENSG00000277791 
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UniProt GroupP49720
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Entity ID: 11
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-2
K, Y
199Homo sapiensMutation(s): 0 
EC: 3.4.25.1
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GTEx:  ENSG00000126067 
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Entity ID: 12
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-5
L, Z
201Homo sapiensMutation(s): 0 
EC: 3.4.25.1
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GTEx:  ENSG00000100804 
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Entity ID: 13
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-1AA [auth 1],
M
213Homo sapiensMutation(s): 0 
EC: 3.4.25.1
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GTEx:  ENSG00000008018 
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Entity ID: 14
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome subunit beta type-4BA [auth 2],
N
217Homo sapiensMutation(s): 0 
EC: 3.4.25.1
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Find proteins for P28070 (Homo sapiens)
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GTEx:  ENSG00000159377 
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UniProt GroupP28070
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Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.206 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 119.227α = 90
b = 205.061β = 106.37
c = 163.128γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-3000data collection
HKL-3000data reduction
SCALEPACKdata scaling
PHENIXphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-01-28
    Type: Initial release
  • Version 1.1: 2015-02-04
    Changes: Database references
  • Version 1.2: 2015-02-18
    Changes: Database references
  • Version 1.3: 2024-02-28
    Changes: Data collection, Database references