2FHH

Crystal Structure of Mycobacterium Tuberculosis Proteasome in complex with a peptidyl boronate inhibitor MLN-273


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.99 Å
  • R-Value Free: 0.262 
  • R-Value Work: 0.226 
  • R-Value Observed: 0.228 

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Ligand Structure Quality Assessment 


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Literature

Structure of the Mycobacterium tuberculosis proteasome and mechanism of inhibition by a peptidyl boronate.

Hu, G.Lin, G.Wang, M.Dick, L.Xu, R.M.Nathan, C.Li, H.

(2006) Mol Microbiol 59: 1417-1428

  • DOI: https://doi.org/10.1111/j.1365-2958.2005.05036.x
  • Primary Citation of Related Structures:  
    2FHG, 2FHH

  • PubMed Abstract: 

    Mycobacterium tuberculosis (Mtb) has the remarkable ability to resist killing by human macrophages. The 750 kDa proteasome, not available in most eubacteria except Actinomycetes, appears to contribute to Mtb's resistance. The crystal structure of the Mtb proteasome at 3.0 A resolution reveals a substrate-binding pocket with composite features of the distinct beta1, beta2 and beta5 substrate binding sites of eukaryotic proteasomes, accounting for the broad specificity of the Mtb proteasome towards oligopeptides described in the companion article [Lin et al. (2006), Mol Microbiol doi:10.1111/j.1365-2958.2005.05035.x]. The substrate entrance at the end of the cylindrical proteasome appears open in the crystal structure due to partial disorder of the alpha-subunit N-terminal residues. However, cryo-electron microscopy of the core particle reveals a closed end, compatible with the density observed in negative-staining electron microscopy that depended on the presence of the N-terminal octapetides of the alpha-subunits in the companion article, suggesting that the Mtb proteasome has a gated structure. We determine for the first time the proteasomal inhibition mechanism of the dipeptidyl boronate N-(4-morpholine)carbonyl-beta-(1-naphthyl)-L-alanine-L-leucine boronic acid (MLN-273), an analogue of the antimyeloma drug bortezomib. The structure improves prospects for designing Mtb-specific proteasomal inhibitors as a novel approach to chemotherapy of tuberculosis.


  • Organizational Affiliation

    Biology Department, Brookhaven National Laboratory, 50 Bell Avenue, Upton, NY 11973, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
20S proteasome, alpha and beta subunits251Mycobacterium tuberculosisMutation(s): 0 
Gene Names: PrcA
UniProt
Find proteins for P9WHU1 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore P9WHU1 
Go to UniProtKB:  P9WHU1
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP9WHU1
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
proteasome, beta subunit240Mycobacterium tuberculosisMutation(s): 0 
Gene Names: PrcB
UniProt
Find proteins for P9WHT9 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore P9WHT9 
Go to UniProtKB:  P9WHT9
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP9WHT9
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
M1N
Query on M1N

Download Ideal Coordinates CCD File 
CA [auth H]
DA [auth C]
EA [auth E]
FA [auth G]
GA [auth J]
CA [auth H],
DA [auth C],
EA [auth E],
FA [auth G],
GA [auth J],
HA [auth L],
IA [auth N],
JA [auth P],
KA [auth R],
LA [auth T],
MA [auth V],
NA [auth X],
OA [auth Z],
PA [auth 2]
(1R)-3-METHYL-1-{[N-(MORPHOLIN-4-YLCARBONYL)-3-(1-NAPHTHYL)-D-ALANYL]AMINO}BUTYLBORONIC ACID
C23 H32 B N3 O5
MQMHIOPMTAJOHV-RTWAWAEBSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.99 Å
  • R-Value Free: 0.262 
  • R-Value Work: 0.226 
  • R-Value Observed: 0.228 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 173.957α = 90
b = 116.172β = 112.71
c = 200.203γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
CBASSdata collection
SCALEPACKdata scaling
CNSphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2006-02-28 
  • Deposition Author(s): Li, H.

Revision History  (Full details and data files)

  • Version 1.0: 2006-02-28
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Advisory, Refinement description, Version format compliance
  • Version 1.3: 2023-08-30
    Changes: Data collection, Database references, Derived calculations, Refinement description