 |
PDBsum entry 4xu3
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Ligase/ligase inhibitor
|
PDB id
|
|
|
|
4xu3
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Ligase/ligase inhibitor
|
|
|
Title:
|
|
Mycobacterium tuberculosis biotin ligase complexed with bisubstrate inhibitor 90 that has an acyclic ether in place of the ribose
|
|
Structure:
|
|
Bifunctional ligase/repressor bira. Chain: a, b. Synonym: biotin--acetyl-coa-carboxylase ligase,biotin-protein ligase, bira protein. Engineered: yes
|
|
Source:
|
|
Mycobacterium tuberculosis. Organism_taxid: 1773. Gene: bira, ch81_03124, ch82_03406, ch84_03412, ch85_03111, ch87_01691, ch88_02592, co60_3782, er17_17395, ff22_02902, fi98_01129, iq38_01820, iq39_01720, iq40_01775, iq41_01700, iq42_01770, iq43_01710, iq44_01750, iq45_01765, iq46_01705, iq47_01735, iq48_01770, iu12_01860, iu13_01785, iu14_01730, iu16_01770, iu17_01745, iu18_01730, iu19_01775, iu20_01750, iu22_01755, iu23_01750, iu24_01735, iz84_17515, je53_17495,
|
|
Resolution:
|
|
|
2.24Å
|
R-factor:
|
0.188
|
R-free:
|
0.232
|
|
|
Authors:
|
|
T.De La Mora-Rey,B.C.Finzel
|
|
Key ref:
|
|
M.R.Bockman
et al.
(2015).
Targeting Mycobacterium tuberculosis Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bisubstrate Adenylation Inhibitors.
J Med Chem,
58,
7349-7369.
PubMed id:
DOI:
|
|
|
Date:
|
|
|
24-Jan-15
|
Release date:
|
02-Sep-15
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
I6YFP0
(I6YFP0_MYCTU) -
Biotin--[acetyl-CoA-carboxylase] ligase from Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
|
|
|
|
Seq:
Struc:
|
|
|
|
266 a.a.
263 a.a.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Key: |
 |
PfamA domain |
|
|
 |
Secondary structure |
|
 |
CATH domain |
|
|
|
|
|
|
|
|
|
|
|
|
|
Enzyme class:
|
|
E.C.6.3.4.15
- biotin--[biotin carboxyl-carrier protein] ligase.
|
|
|
|
|
|
|
Reaction:
|
|
biotin + L-lysyl-[protein] + ATP = N6-biotinyl-L-lysyl-[protein] + AMP + diphosphate + H+
|
|
|
|
|
|
biotin
|
+
|
L-lysyl-[protein]
Bound ligand (Het Group name = )
matches with 42.86% similarity
|
+
|
ATP
|
=
|
N(6)-biotinyl-L-lysyl-[protein]
|
+
|
AMP
|
+
|
diphosphate
|
+
|
H(+)
|
|
|
|
|
|
|
|
|
|
|
|
|
Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
|
| |
|
DOI no:
|
J Med Chem
58:7349-7369
(2015)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Targeting Mycobacterium tuberculosis Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bisubstrate Adenylation Inhibitors.
|
|
M.R.Bockman,
A.S.Kalinda,
R.Petrelli,
T.De la Mora-Rey,
D.Tiwari,
F.Liu,
S.Dawadi,
M.Nandakumar,
K.Y.Rhee,
D.Schnappinger,
B.C.Finzel,
C.C.Aldrich.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
Mycobacterium tuberculosis (Mtb), responsible for both latent and symptomatic
tuberculosis (TB), remains the second leading cause of mortality among
infectious diseases worldwide. Mycobacterial biotin protein ligase (MtBPL) is an
essential enzyme in Mtb and regulates lipid metabolism through the
post-translational biotinylation of acyl coenzyme A carboxylases. We report the
synthesis and evaluation of a systematic series of potent nucleoside-based
inhibitors of MtBPL that contain modifications to the ribofuranosyl ring of the
nucleoside. All compounds were characterized by isothermal titration calorimetry
(ITC) and shown to bind potently with KDs ≤ 2 nM. Additionally, we obtained
high-resolution cocrystal structures for a majority of the compounds. Despite
fairly uniform biochemical potency, the whole-cell Mtb activity varied greatly
with minimum inhibitory concentrations (MIC) ranging from 0.78 to >100 μM.
Cellular accumulation studies showed a nearly 10-fold enhancement in
accumulation of a C-2'-α analogue over the corresponding C-2'-β analogue,
consistent with their differential whole-cell activity.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Links
