 |
PDBsum entry 6qos
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Transferase
|
|
|
Title:
|
|
Crystal structure of trmd, a tRNA-(n1g37) methyltransferase, from mycobacterium abscessus in complex with fragment 22 (ethyl 1h- pyrazole-4-carboxylate)
|
|
Structure:
|
|
tRNA (guanine-n(1)-)-methyltransferase. Chain: a, b. Synonym: m1g-methyltransferase,tRNA [gm37] methyltransferase. Engineered: yes
|
|
Source:
|
|
Mycobacterium abscessus. Organism_taxid: 36809. Atcc: 19977. Gene: trmd, mab_3226c. Expressed in: escherichia coli. Expression_system_taxid: 562
|
|
Resolution:
|
|
|
2.05Å
|
R-factor:
|
0.193
|
R-free:
|
0.229
|
|
|
Authors:
|
|
S.E.Thomas,A.J.Whitehouse,A.G.Coyne,C.Abell,V.Mendes,T.L.Blundell
|
|
Key ref:
|
|
S.E.Thomas
et al.
(2020).
Fragment-based discovery of a new class of inhibitors targeting mycobacterial tRNA modification.
Nucleic Acids Res,
48,
8099-8112.
PubMed id:
DOI:
|
|
|
Date:
|
|
|
12-Feb-19
|
Release date:
|
26-Feb-20
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
B1MDI3
(B1MDI3_MYCA9) -
tRNA (guanine-N(1)-)-methyltransferase from Mycobacteroides abscessus (strain ATCC 19977 / DSM 44196 / CCUG 20993 / CIP 104536 / JCM 13569 / NCTC 13031 / TMC 1543 / L948)
|
|
|
|
Seq:
Struc:
|
|
|
|
242 a.a.
211 a.a.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Key: |
 |
PfamA domain |
|
|
 |
Secondary structure |
|
|
|
|
|
|
|
|
|
|
|
|
|
Enzyme class:
|
|
E.C.2.1.1.228
- tRNA (guanine(37)-N(1))-methyltransferase.
|
|
|
|
|
|
|
Reaction:
|
|
guanosine37 in tRNA + S-adenosyl-L-methionine = N1- methylguanosine37 in tRNA + S-adenosyl-L-homocysteine + H+
|
|
|
|
|
|
guanosine(37) in tRNA
|
+
|
S-adenosyl-L-methionine
|
=
|
N(1)- methylguanosine(37) in tRNA
|
+
|
S-adenosyl-L-homocysteine
|
+
|
H(+)
|
|
|
|
|
|
|
|
|
|
|
|
|
Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
|
| |
|
DOI no:
|
Nucleic Acids Res
48:8099-8112
(2020)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Fragment-based discovery of a new class of inhibitors targeting mycobacterial tRNA modification.
|
|
S.E.Thomas,
A.J.Whitehouse,
K.Brown,
S.Burbaud,
J.M.Belardinelli,
J.Sangen,
R.Lahiri,
M.D.J.Libardo,
P.Gupta,
S.Malhotra,
H.I.M.Boshoff,
M.Jackson,
C.Abell,
A.G.Coyne,
T.L.Blundell,
R.A.Floto,
V.Mendes.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
Translational frameshift errors are often deleterious to the synthesis of
functional proteins and could therefore be promoted therapeutically to kill
bacteria. TrmD (tRNA-(N(1)G37) methyltransferase) is an essential tRNA
modification enzyme in bacteria that prevents +1 errors in the reading frame
during protein translation and represents an attractive potential target for the
development of new antibiotics. Here, we describe the application of a
structure-guided fragment-based drug discovery approach to the design of a new
class of inhibitors against TrmD in Mycobacterium abscessus. Fragment library
screening, followed by structure-guided chemical elaboration of hits, led to the
rapid development of drug-like molecules with potent in vitro TrmD inhibitory
activity. Several of these compounds exhibit activity against planktonic M.
abscessus and M. tuberculosis as well as against intracellular M. abscessus and
M. leprae, indicating their potential as the basis for a novel class of
broad-spectrum mycobacterial drugs.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Links
