1M0E

ZEBULARINE: A NOVEL DNA METHYLATION INHIBITOR THAT FORMS A COVALENT COMPLEX WITH DNA METHYLTRANSFERASE

Summary for 1M0E

• Entry DOI: 10.2210/pdb1m0e/pdb
• Related: 9MHT
• Descriptor: 5'-D(P*CP*CP*AP*TP*GP*CP*GP*CP*TP*GP*AP*C)-3', 5'-D(P*GP*TP*CP*AP*GP*(Z)P*GP*CP*AP*TP*GP*G)-3', Modification methylase HhaI, ... (5 entities in total)
• Functional Keywords: protein-dna covalent complex, mechanism based dna methylation inhibitors, zebularine, transferase-dna complex, transferase/dna
• Biological source: Haemophilus haemolyticus
• Total number of polymer chains: 3
• Total formula weight: 44738.39

Authors

Zhou, L.,Cheng, X.,Connolly, B.A.,Dickman, M.J.,Hurd, P.J.,Hornby, D.P. (deposition date: 2002-06-12, release date: 2002-09-18, Last modification date: 2024-10-30)

Primary citation

Zhou, L.,Cheng, X.,Connolly, B.A.,Dickman, M.J.,Hurd, P.J.,Hornby, D.P.
ZEBULARINE: A NOVEL DNA METHYLATION INHIBITOR THAT FORMS A COVALENT COMPLEX WITH DNA METHYLTRANSFERASES
J.MOL.BIOL., 321:591-599, 2002

PubMed Abstract: Mechanism-based inhibitors of enzymes, which mimic reactive intermediates in the reaction pathway, have been deployed extensively in the analysis of metabolic pathways and as candidate drugs. The inhibition of cytosine-[C5]-specific DNA methyltransferases (C5 MTases) by oligodeoxynucleotides containing 5-azadeoxycytidine (AzadC) and 5-fluorodeoxycytidine (FdC) provides a well-documented example of mechanism-based inhibition of enzymes central to nucleic acid metabolism. Here, we describe the interaction between the C5 MTase from Haemophilus haemolyticus (M.HhaI) and an oligodeoxynucleotide duplex containing 2-H pyrimidinone, an analogue often referred to as zebularine and known to give rise to high-affinity complexes with MTases. X-ray crystallography has demonstrated the formation of a covalent bond between M.HhaI and the 2-H pyrimidinone-containing oligodeoxynucleotide. This observation enables a comparison between the mechanisms of action of 2-H pyrimidinone with other mechanism-based inhibitors such as FdC. This novel complex provides a molecular explanation for the mechanism of action of the anti-cancer drug zebularine.

PubMed: 12206775
DOI: 10.1016/S0022-2836(02)00676-9

Experimental method

X-RAY DIFFRACTION (2.5 Å)