PDBsum entry 4mcb

Transferase/transferase inhibitor

PDB id: 4mcb

Contents

Protein chains

205 a.a.

243 a.a.

Ligands

GOL

SO4 ×2

21W ×2

ACT

Waters ×575

PDB id:

4mcb

Name:

Transferase/transferase inhibitor

Title:

H.Influenzae trmd in complex with n-(4-{[(1h-imidazol-2-ylmethyl) amino]methyl}benzyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-5- carboxamide

Structure:

tRNA (guanine-n(1)-)-methyltransferase. Chain: a, b. Synonym: m1g-methyltransferase, tRNA [gm37] methyltransferase. Engineered: yes

Source:

Haemophilus influenzae. Organism_taxid: 71421. Strain: atcc51907. Gene: hi_0202, trmd. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.94Å R-factor: 0.180 R-free: 0.205

Authors:

N.B.Olivier,P.Hill

Key ref:

P.J.Hill et al. (2013). Selective inhibitors of bacterial t-RNA-(N(1)G37) methyltransferase (TrmD) that demonstrate novel ordering of the lid domain. J Med Chem, 56, 7278-7288. PubMed id: 23981144 DOI: 10.1021/jm400718n

Date:

21-Aug-13 Release date: 04-Sep-13

Protein chain

P43912  (TRMD_HAEIN) -  tRNA (guanine-N(1)-)-methyltransferase from Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd)

Seq: 246 a.a.

Struc: 205 a.a.

Protein chain

P43912  (TRMD_HAEIN) -  tRNA (guanine-N(1)-)-methyltransferase from Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd)

Seq: 246 a.a.

Struc: 243 a.a.

Enzyme reactions

• Enzyme class: Chains A, B: 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⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1021/jm400718n

J Med Chem 56:7278-7288 (2013)

PubMed id: 23981144

Selective inhibitors of bacterial t-RNA-(N(1)G37) methyltransferase (TrmD) that demonstrate novel ordering of the lid domain.

P.J.Hill, A.Abibi, R.Albert, B.Andrews, M.M.Gagnon, N.Gao, T.Grebe, L.I.Hajec, J.Huang, S.Livchak, S.D.Lahiri, D.C.McKinney, J.Thresher, H.Wang, N.Olivier, E.T.Buurman.

ABSTRACT

The tRNA-(N(1)G37) methyltransferase (TrmD) is essential for growth and highly conserved in both Gram-positive and Gram-negative bacterial pathogens. Additionally, TrmD is very distinct from its human orthologue TRM5 and thus is a suitable target for the design of novel antibacterials. Screening of a collection of compound fragments using Haemophilus influenzae TrmD identified inhibitory, fused thieno-pyrimidones that were competitive with S-adenosylmethionine (SAM), the physiological methyl donor substrate. Guided by X-ray cocrystal structures, fragment 1 was elaborated into a nanomolar inhibitor of a broad range of Gram-negative TrmD isozymes. These compounds demonstrated no activity against representative human SAM utilizing enzymes, PRMT1 and SET7/9. This is the first report of selective, nanomolar inhibitors of TrmD with demonstrated ability to order the TrmD lid in the absence of tRNA.