PMID- 32673148
OWN - NLM
STAT- MEDLINE
DCOM- 20211021
LR  - 20211021
IS  - 1538-0254 (Electronic)
IS  - 0739-1102 (Linking)
VI  - 39
IP  - 15
DP  - 2021 Sep
TI  - Dynamics and allostery of Zika virus non-structural protein 5 methyltransferase.
PG  - 5526-5538
LID - 10.1080/07391102.2020.1792343 [doi]
AB  - The methyltransferase (MTase) domain of non-structural protein 5 (NS5) plays a 
      fundamental role in flaviviruses replication, and its inhibition is a strategy 
      for antiviral development. MTase methylates viral RNA cap at guanine N-7 and the 
      ribose 2'OH of the first adenosine. Many structures of Zika virus (ZIKV) and 
      other flaviviruses MTases bound to cofactors, substrates and inhibitor candidates 
      have been solved. Still, the dynamical modulation of MTase binding and catalytic 
      activity yet needs to be clarified. Here, we investigated the structural dynamics 
      of ZIKV NS5 MTase domain free and bound to Guanosine-5'-triphosphate (GTP) and 
      S-Adenosyl-Lmethionine (SAM), to identify the molecular dynamics changes related 
      to ligand binding and methyl transfer reaction. We have observed that the binding 
      of the GTP and SAM individually and GTP-SAM in the ternary complex has induced 
      allostery in the RNA binding site, showing the complexity of ZIKV MTase 
      conformational equilibrium and its impact on viral RNA recognition. We also 
      mapped in molecular dynamics trajectories, conformations of GTP guanine moiety 
      that mimics guanine orientations visualized in human-specific N-methyltransferase 
      structures solved by X-ray crystallography. It is the first time that N-7 
      methylation-prone guanine orientation has been proposed and modeled in flavivirus 
      MTase. Communicated by Ramaswamy H. Sarma.
FAU - Chagas, Marcelo
AU  - Chagas M
AD  - Departamento de Quimica, ICEx, Universidade Federal de Minas Gerais, Belo 
      Horizonte, Brazil.
FAU - Rocha, Willian
AU  - Rocha W
AUID- ORCID: 0000-0002-0025-2158
AD  - Departamento de Quimica, ICEx, Universidade Federal de Minas Gerais, Belo 
      Horizonte, Brazil.
FAU - Moraes, Adolfo
AU  - Moraes A
AUID- ORCID: 0000-0002-3344-4084
AD  - Departamento de Quimica, ICEx, Universidade Federal de Minas Gerais, Belo 
      Horizonte, Brazil.
AD  - Department of NMR-based Structural Biology, Max-Planck Institute for Biophysical 
      Chemistry, Gottingen, Germany.
LA  - eng
PT  - Journal Article
DEP - 20200716
PL  - England
TA  - J Biomol Struct Dyn
JT  - Journal of biomolecular structure & dynamics
JID - 8404176
RN  - 0 (Viral Nonstructural Proteins)
RN  - EC 2.1.1.- (Methyltransferases)
SB  - IM
MH  - Humans
MH  - Methyltransferases
MH  - Models, Molecular
MH  - Viral Nonstructural Proteins
MH  - *Zika Virus
MH  - *Zika Virus Infection
OTO - NOTNLM
OT  - RNA methylation
OT  - Zika virus
OT  - methyltransferase
OT  - molecular dynamics
OT  - non-structural protein 5
EDAT- 2020/07/17 06:00
MHDA- 2023/02/25 06:00
CRDT- 2020/07/17 06:00
PHST- 2020/07/17 06:00 [pubmed]
PHST- 2023/02/25 06:00 [medline]
PHST- 2020/07/17 06:00 [entrez]
AID - 10.1080/07391102.2020.1792343 [doi]
PST - ppublish
SO  - J Biomol Struct Dyn. 2021 Sep;39(15):5526-5538. doi: 
      10.1080/07391102.2020.1792343. Epub 2020 Jul 16.