3P8Z

Dengue Methyltransferase bound to a SAM-based inhibitor

3P8Z の概要

• エントリーDOI: 10.2210/pdb3p8z/pdb
• 関連するPDBエントリー: 3P97
• 分子名称: 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)
• 機能のキーワード: methyltransferase, rna, er, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Dengue virus 3
• 細胞内の位置: Envelope protein E: Virion membrane; Multi- pass membrane protein: C1KBQ3
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 61032.56

構造登録者

Noble, C.G.,Yap, L.J.,Lescar, J. (登録日: 2010-10-15, 公開日: 2010-12-08, 最終更新日: 2023-11-01)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.7 Å)