3P8Z

Dengue Methyltransferase bound to a SAM-based inhibitor

Summary for 3P8Z

• Entry DOI: 10.2210/pdb3p8z/pdb
• Related: 3P97
• Descriptor: Non-structural protein 5, (S)-2-amino-4-(((2S,3S,4R,5R)-5-(6-(3-chlorobenzylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methylthio)butanoic acid, S-ADENOSYL-L-HOMOCYSTEINE, ... (4 entities in total)
• Functional Keywords: methyltransferase, rna, er, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Dengue virus 3
• Cellular location: Envelope protein E: Virion membrane; Multi- pass membrane protein: C1KBQ3
• Total number of polymer chains: 2
• Total formula weight: 61032.56

Authors

Noble, C.G.,Yap, L.J.,Lescar, J. (deposition date: 2010-10-15, release date: 2010-12-08, Last modification date: 2023-11-01)

Primary citation

Lim, S.P.,Sonntag, L.S.,Noble, C.,Nilar, S.H.,Ng, R.H.,Zou, G.,Monaghan, P.,Chung, K.Y.,Dong, H.,Liu, B.,Bodenreider, C.,Lee, G.,Ding, M.,Chan, W.L.,Wang, G.,Jian, Y.L.,Chao, A.T.,Lescar, J.,Yin, Z.,Vedananda, T.R.,Keller, T.H.,Shi, P.Y.
Small molecule inhibitors that selectively block dengue virus methyltransferase
J.Biol.Chem., 286:6233-6240, 2011

PubMed Abstract: Crystal structure analysis of Flavivirus methyltransferases uncovered a flavivirus-conserved cavity located next to the binding site for its cofactor, S-adenosyl-methionine (SAM). Chemical derivatization of S-adenosyl-homocysteine (SAH), the product inhibitor of the methylation reaction, with substituents that extend into the identified cavity, generated inhibitors that showed improved and selective activity against dengue virus methyltransferase (MTase), but not related human enzymes. Crystal structure of dengue virus MTase with a bound SAH derivative revealed that its N6-substituent bound in this cavity and induced conformation changes in residues lining the pocket. These findings demonstrate that one of the major hurdles for the development of methyltransferase-based therapeutics, namely selectivity for disease-related methyltransferases, can be overcome.

PubMed: 21147775
DOI: 10.1074/jbc.M110.179184

Experimental method

X-RAY DIFFRACTION (1.7 Å)