3P8Z

Dengue Methyltransferase bound to a SAM-based inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.199 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Small molecule inhibitors that selectively block dengue virus methyltransferase

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.

(2011) J Biol Chem 286: 6233-6240

  • DOI: https://doi.org/10.1074/jbc.M110.179184
  • Primary Citation of Related Structures:  
    3P8Z, 3P97

  • 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.


  • Organizational Affiliation

    Novartis Institute for Tropical Diseases, 05-01 Chromos, Singapore. siew_pheng.lim@novartis.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Non-structural protein 5A,
B [auth C]
267dengue virus type 3Mutation(s): 0 
EC: 2.1.1.56 (PDB Primary Data), 2.1.1.57 (PDB Primary Data)
UniProt
Find proteins for P27915 (Dengue virus type 3 (strain Philippines/H87/1956))
Explore P27915 
Go to UniProtKB:  P27915
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP27915
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
36A
Query on 36A

Download Ideal Coordinates CCD File 
C [auth A](S)-2-amino-4-(((2S,3S,4R,5R)-5-(6-(3-chlorobenzylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methylthio)butanoic acid
C21 H25 Cl N6 O5 S
VGYBDYWAAOWMTJ-SWQDORGXSA-N
SAH
Query on SAH

Download Ideal Coordinates CCD File 
D [auth C]S-ADENOSYL-L-HOMOCYSTEINE
C14 H20 N6 O5 S
ZJUKTBDSGOFHSH-WFMPWKQPSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
36A PDBBind:  3P8Z Ki: 820 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.199 
  • Space Group: P 2 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 51.811α = 90
b = 61.095β = 90
c = 184.683γ = 90
Software Package:
Software NamePurpose
REFMACrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-12-08
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2011-09-28
    Changes: Database references
  • Version 1.3: 2023-11-01
    Changes: Data collection, Database references, Derived calculations, Refinement description