RCSB PDB - 5CZ5: Yeast 20S proteasome beta1-T1A mutant in complex with Carfilzomib

 5CZ5

Yeast 20S proteasome beta1-T1A mutant in complex with Carfilzomib


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.222 
  • R-Value Work: 0.201 
  • R-Value Observed: 0.202 

Starting Model: experimental
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Literature

A unified mechanism for proteolysis and autocatalytic activation in the 20S proteasome.

Huber, E.M.Heinemeyer, W.Li, X.Arendt, C.S.Hochstrasser, M.Groll, M.

(2016) Nat Commun 7: 10900-10900

  • DOI: https://doi.org/10.1038/ncomms10900
  • Primary Citation of Related Structures:  
    5CZ4, 5CZ5, 5CZ6, 5CZ7, 5CZ8, 5CZ9, 5CZA, 5D0S, 5D0T, 5D0V, 5D0W, 5D0X, 5D0Z, 5FG7, 5FG9, 5FGA, 5FGD, 5FGE, 5FGF, 5FGG, 5FGH, 5FGI, 5FHS

  • PubMed Abstract: 

    Biogenesis of the 20S proteasome is tightly regulated. The N-terminal propeptides protecting the active-site threonines are autocatalytically released only on completion of assembly. However, the trigger for the self-activation and the reason for the strict conservation of threonine as the active site nucleophile remain enigmatic. Here we use mutagenesis, X-ray crystallography and biochemical assays to suggest that Lys33 initiates nucleophilic attack of the propeptide by deprotonating the Thr1 hydroxyl group and that both residues together with Asp17 are part of a catalytic triad. Substitution of Thr1 by Cys disrupts the interaction with Lys33 and inactivates the proteasome. Although a Thr1Ser mutant is active, it is less efficient compared with wild type because of the unfavourable orientation of Ser1 towards incoming substrates. This work provides insights into the basic mechanism of proteolysis and propeptide autolysis, as well as the evolutionary pressures that drove the proteasome to become a threonine protease.


  • Organizational Affiliation

    Center for Integrated Protein Science at the Department Chemie, Lehrstuhl für Biochemie, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, 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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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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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
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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
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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
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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
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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
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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
206Saccharomyces cerevisiae S288CMutation(s): 1 
EC: 3.4.25.1
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Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3BV
Query on 3BV

Download Ideal Coordinates CCD File 
FA [auth H],
JA [auth K],
QA [auth V],
SA [auth Y]
N-{(2S)-2-[(morpholin-4-ylacetyl)amino]-4-phenylbutanoyl}-L-leucyl-N-[(2R,3S,4S)-1,3-dihydroxy-2,6-dimethylheptan-4-yl]-L-phenylalaninamide
C40 H61 N5 O7
CNNZTHKANUECTE-JMNVNGPASA-N
MES
Query on MES

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GA [auth H],
LA [auth K],
RA [auth V],
TA [auth Y]
2-(N-MORPHOLINO)-ETHANESULFONIC ACID
C6 H13 N O4 S
SXGZJKUKBWWHRA-UHFFFAOYSA-N
CL
Query on CL

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EA [auth G],
OA [auth N],
PA [auth U],
VA [auth b]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
MG
Query on MG

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CA [auth G]
DA [auth G]
HA [auth I]
IA [auth I]
KA [auth K]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.222 
  • R-Value Work: 0.201 
  • R-Value Observed: 0.202 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 136.77α = 90
b = 300.42β = 113.14
c = 145.34γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
XSCALEdata scaling
REFMACphasing
REFMACrefinement

Structure Validation

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Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted 3BVClick on this verticalbar to view details

Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
German Research FoundationGermanySFB1035/A2

Revision History  (Full details and data files)

  • Version 1.0: 2016-03-23
    Type: Initial release
  • Version 1.1: 2016-12-21
    Changes: Non-polymer description
  • Version 1.2: 2018-11-07
    Changes: Author supporting evidence, Data collection, Source and taxonomy, Structure summary
  • Version 1.3: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Refinement description
  • Version 1.4: 2024-11-06
    Changes: Structure summary