3p8z
From Proteopedia
Dengue Methyltransferase bound to a SAM-based inhibitor
Structural highlights
Function[C1KBQ3_9FLAV] Envelope protein E binding to host cell surface receptor is followed by virus internalization through clathrin-mediated endocytosis. Envelope protein E is subsequently involved in membrane fusion between virion and host late endosomes. Synthesized as a homodimer with prM which acts as a chaperone for envelope protein E. After cleavage of prM, envelope protein E dissociate from small envelope protein M and homodimerizes (By similarity).[SAAS:SAAS026470_004_099774] Publication Abstract from PubMedCrystal 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. Small molecule inhibitors that selectively block dengue virus methyltransferase.,Lim SP, Sonntag LS, Noble C, Nilar SH, Ng RH, Zou G, Monaghan P, Chung KY, Dong H, Liu B, Bodenreider C, Lee G, Ding M, Chan WL, Wang G, Jian YL, Chao AT, Lescar J, Yin Z, Vedananda TR, Keller TH, Shi PY J Biol Chem. 2011 Feb 25;286(8):6233-40. Epub 2010 Dec 8. PMID:21147775[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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