4MCC

HinTrmD in complex with N-[4-(AMINOMETHYL)BENZYL]-4-OXO-3,4-DIHYDROTHIENO[2,3-D]PYRIMIDINE-5-CARBOXAMIDE

Summary for 4MCC

• Entry DOI: 10.2210/pdb4mcc/pdb
• Related: 4MDB
• Descriptor: tRNA (guanine-N(1)-)-methyltransferase, N-[4-(aminomethyl)benzyl]-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-5-carboxamide (3 entities in total)
• Functional Keywords: trefoil, trmd, sam, sah, sinefungin, hmt, structural genomics, n/a, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Haemophilus influenzae
• Cellular location: Cytoplasm (Potential): P43912
• Total number of polymer chains: 2
• Total formula weight: 55786.02

Authors

Olivier, N.B.,Hill, P. (deposition date: 2013-08-21, release date: 2013-09-04, Last modification date: 2024-02-28)

Primary citation

Hill, P.J.,Abibi, A.,Albert, R.,Andrews, B.,Gagnon, M.M.,Gao, N.,Grebe, T.,Hajec, L.I.,Huang, J.,Livchak, S.,Lahiri, S.D.,McKinney, D.C.,Thresher, J.,Wang, H.,Olivier, N.,Buurman, E.T.
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, 2013

PubMed 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.

PubMed: 23981144
DOI: 10.1021/jm400718n

Experimental method

X-RAY DIFFRACTION (1.95 Å)