3H6I

Crystal Structure of Mycobacterium Tuberculosis Proteasome Modified by inhibitor GL1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.43 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.204 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Inhibitors selective for mycobacterial versus human proteasomes.

Lin, G.Li, D.de Carvalho, L.P.Deng, H.Tao, H.Vogt, G.Wu, K.Schneider, J.Chidawanyika, T.Warren, J.D.Li, H.Nathan, C.

(2009) Nature 461: 621-626

  • DOI: https://doi.org/10.1038/nature08357
  • Primary Citation of Related Structures:  
    3H6F, 3H6I, 3HF9, 3HFA

  • PubMed Abstract: 

    Many anti-infectives inhibit the synthesis of bacterial proteins, but none selectively inhibits their degradation. Most anti-infectives kill replicating pathogens, but few preferentially kill pathogens that have been forced into a non-replicating state by conditions in the host. To explore these alternative approaches we sought selective inhibitors of the proteasome of Mycobacterium tuberculosis. Given that the proteasome structure is extensively conserved, it is not surprising that inhibitors of all chemical classes tested have blocked both eukaryotic and prokaryotic proteasomes, and no inhibitor has proved substantially more potent on proteasomes of pathogens than of their hosts. Here we show that certain oxathiazol-2-one compounds kill non-replicating M. tuberculosis and act as selective suicide-substrate inhibitors of the M. tuberculosis proteasome by cyclocarbonylating its active site threonine. Major conformational changes protect the inhibitor-enzyme intermediate from hydrolysis, allowing formation of an oxazolidin-2-one and preventing regeneration of active protease. Residues outside the active site whose hydrogen bonds stabilize the critical loop before and after it moves are extensively non-conserved. This may account for the ability of oxathiazol-2-one compounds to inhibit the mycobacterial proteasome potently and irreversibly while largely sparing the human homologue.


  • Organizational Affiliation

    Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York 10065, USA. [email protected]


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome (Alpha subunit) PrcA
A,
AA [auth 1],
B,
D,
F,
I,
K,
M,
O,
Q,
S,
U,
W,
Y
248Mycobacterium tuberculosisMutation(s): 0 
Gene Names: prcARv2109c
EC: 3.4.25.1
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
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Proteasome (Beta subunit) PrcB
BA [auth 2],
C,
E,
G,
H,
J,
L,
N,
P,
R,
T,
V,
X,
Z
240Mycobacterium tuberculosisMutation(s): 0 
Gene Names: MT2170prcBRv2110c
EC: 3.4.25.1
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
DMF
Query on DMF

Download Ideal Coordinates CCD File 
AB [auth F]
AC [auth N]
AD [auth U]
BB [auth G]
BC [auth N]
AB [auth F],
AC [auth N],
AD [auth U],
BB [auth G],
BC [auth N],
BD [auth U],
CA [auth A],
CB [auth G],
CC [auth N],
CD [auth U],
DA [auth A],
DB [auth G],
DC [auth N],
DD [auth U],
EA [auth B],
EB [auth G],
EC [auth N],
ED [auth V],
FA [auth B],
FB [auth H],
FC [auth O],
FD [auth V],
GA [auth B],
GB [auth H],
GC [auth O],
GD [auth V],
HA [auth C],
HB [auth H],
HC [auth P],
HD [auth V],
IA [auth C],
IB [auth H],
IC [auth P],
ID [auth W],
JA [auth C],
JB [auth H],
JC [auth P],
JD [auth W],
KA [auth C],
KB [auth H],
KC [auth P],
KD [auth X],
LA [auth C],
LB [auth H],
LC [auth P],
LD [auth X],
MA [auth C],
MB [auth I],
MC [auth Q],
MD [auth X],
NA [auth C],
NB [auth I],
NC [auth Q],
ND [auth Y],
OA [auth C],
OB [auth J],
OC [auth R],
OD [auth Z],
PA [auth D],
PB [auth J],
PC [auth R],
PD [auth Z],
QA [auth D],
QB [auth J],
QC [auth R],
QD [auth Z],
RA [auth D],
RB [auth K],
RC [auth R],
RD [auth Z],
SA [auth D],
SB [auth K],
SC [auth S],
SD [auth Z],
TA [auth E],
TB [auth L],
TC [auth S],
TD [auth Z],
UA [auth E],
UB [auth L],
UC [auth S],
UD [auth 1],
VA [auth E],
VB [auth L],
VC [auth T],
VD [auth 1],
WA [auth E],
WB [auth M],
WC [auth T],
WD [auth 1],
XA [auth E],
XB [auth M],
XC [auth T],
XD [auth 2],
YA [auth E],
YB [auth N],
YC [auth T],
YD [auth 2],
ZA [auth F],
ZB [auth N],
ZC [auth T],
ZD [auth 2]
DIMETHYLFORMAMIDE
C3 H7 N O
ZMXDDKWLCZADIW-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.43 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.204 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 171.615α = 90
b = 117.667β = 113.65
c = 196.335γ = 90
Software Package:
Software NamePurpose
CBASSdata collection
CNSrefinement
HKL-2000data reduction
HKL-2000data scaling
CNSphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-09-15
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description
  • Version 1.3: 2023-11-22
    Changes: Data collection