Molecular insight into the specific binding of ADP-ribose to the nsP3 macro domains of chikungunya and venezuelan equine encephalitis viruses: Molecular dynamics simulations and free energy calculations

Rungrotmongkol, Thanyada; Nunthaboot, Nadtanet; Malaisree, Maturos; Kaiyawet, Nopporn; Yotmanee, Pathumwadee; Meeprasert, Arthitaya; Hannongbua, Supot

doi:10.1016/j.jmgm.2010.09.010

Cited by 49 publications

(46 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This protein is an integral element of the alphavirus replication complexes, in which it interacts with other nsPs, and mutations in the nsP3-encoding sequence affect synthesis of the subgenomic RNA. The amino-terminal domain of nsP3, which is termed the macro domain (or X domain), is homologous to similar domains found in the proteins of other viruses with RNA-positive genomes in bacterial and some cellular proteins (33,35). It has been experimentally demonstrated that nsP3 is capable of binding ADP-ribose, poly-ADP-ribose and short single-stranded RNA (ssRNA), although this has been shown to be a low-affinity interaction, and its biological significance is unclear (33).…”

Section: Discussionmentioning

confidence: 99%

“…Crystal structures of more conserved amino-terminal nsP3 domains (macro domains) of VEEV and CHIKV and a fragment of SINV nsP2 followed by the conserved domain of nsP3 were solved (33,34). The macro domain was found to exhibit a high level of similarity with the ADP-ribose 1Љ-phosphate phosphatases in terms of protein folding (33,35). In biochemical tests, it demonstrated some activities characteristic of the human homologs of the enzyme (33).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Hypervariable Domain of Nonstructural Protein nsP3 of Venezuelan Equine Encephalitis Virus Determines Cell-Specific Mode of Virus Replication

Foy

Akhrymuk

Shustov

et al. 2013

J Virol

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Hypervariable Domain of Nonstructural Protein nsP3 of Venezuelan Equine Encephalitis Virus Determines Cell-Specific Mode of Virus Replication

Foy

Akhrymuk

Shustov

et al. 2013

J Virol

View full text Add to dashboard Cite

“…1A). The binding model was further validated by a rigorous binding free energy calculation; namely, the MM-PBSA method (Rastelli et al 2010), which has been employed for estimating the relative binding free energy of protein with peptide and protein with small molecules (Kollman et al 2000), including the BRCA1 with phospho-peptides (Anisimov et al 2011) and viruses with ADP-ribose (Rungrotmongkol et al 2010) reported recently. Of note, such calculations provide estimates of the relative binding free energy but not the absolute binding free energy of the protein with a ligand.…”

Section: Computational Analysis Of the Par-binding Pockets In The Fhamentioning

confidence: 99%

The FHA and BRCT domains recognize ADP-ribosylation during DNA damage response

et al. 2013

View full text Add to dashboard Cite

Poly-ADP-ribosylation is a unique post-translational modification participating in many biological processes, such as DNA damage response. Here, we demonstrate that a set of Forkhead-associated (FHA) and BRCA1 C-terminal (BRCT) domains recognizes poly(ADP-ribose) (PAR) both in vitro and in vivo. Among these FHA and BRCT domains, the FHA domains of APTX and PNKP interact with iso-ADP-ribose, the linkage of PAR, whereas the BRCT domains of Ligase4, XRCC1, and NBS1 recognize ADP-ribose, the basic unit of PAR. The interactions between PAR and the FHA or BRCT domains mediate the relocation of these domain-containing proteins to DNA damage sites and facilitate the DNA damage response. Moreover, the interaction between PAR and the NBS1 BRCT domain is important for the early activation of ATM during DNA damage response and ATM-dependent cell cycle checkpoint activation. Taken together, our results demonstrate two novel PAR-binding modules that play important roles in DNA damage response.

show abstract

“…The criterion for a hydrogen bond in a given structure was a maximum distance of 3.5 Å between hydrogen donor (D) and acceptor (A) atoms and the angle D-H…A must be greater than 120° [17]. A cutoff distance of 4.0 Å was used in monitoring hydrophobic contacts between the non-polar parts of residues of the nsP2 protease and ligands [40,41].…”

Section: Atomic Details Of Interaction Between the Nsp2 Protein And Hmentioning

confidence: 99%

“…The envelope glycoproteins are involved with viral entry while the non-structural proteins are essential components and play a crucial role in viral replication and transcription [10,16]. Therefore, they are considered as potential targets which several studies utilized to identify potential inhibitors against CHIKV [10,[17][18][19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Identification of chikungunya virus nsP2 protease inhibitors using structure-base approaches

Nguyen¹,

Yu²,

Keller³

2015

Journal of Molecular Graphics and Modelling

View full text Add to dashboard Cite

. (2015). Identification of chikungunya virus nsP2 protease inhibitors using structure-base approaches. Journal of Molecular Graphics and Modelling, 57 1-8. Identification of chikungunya virus nsP2 protease inhibitors using structure-base approaches AbstractThe nsP2 protease of chikungunya virus (CHIKV) is one of the essential components of viral replication and it plays a crucial role in the cleavage of polyprotein precursors for the viral replication process. Therefore, it is gaining attention as a potential drug design target against CHIKV. Based on the recently determined crystal structure of the nsP2 protease of CHIKV, this study identified potential inhibitors of the virus using structurebased approaches with a combination of molecular docking, virtual screening and molecular dynamics (MD) simulations. The top hit compounds from database searching, using the NCI Diversity Set II, with targeting at five potential binding sites of the nsP2 protease, were identified by blind dockings and focused dockings. These complexes were then subjected to MD simulations to investigate the stability and flexibility of the complexes and to gain a more detailed insight into the interactions between the compounds and the enzyme. The hydrogen bonds and hydrophobic contacts were characterized for the complexes. Through structural alignment, the catalytic residues Cys1013 and His1083 were identified in the N-terminal region of the nsP2 protease. The absolute binding free energies were estimated by the linear interaction energy approach and compared with the binding affinities predicted with docking. The results provide valuable information for the development of inhibitors for CHIKV. AbstractThe nsP2 protease of chikungunya virus (CHIKV) is one of the essential components of viral replication and it plays a crucial role in the cleavage of polyprotein precursors for the viral replication process. Therefore, it is gaining attention as a potential drug design target against CHIKV. Based on the recently determined crystal structure of the nsP2 protease of CHIKV, this study identified potential inhibitors of the virus using structure-based approaches with a combination of molecular docking, virtual screening and molecular dynamics (MD) simulations.The top hit compounds from database searching, using the NCI Diversity Set II, with targeting at five potential binding sites of the nsP2 protease, were identified by blind dockings and focused dockings. These complexes were then subjected to MD simulations to investigate the stability and flexibility of the complexes and to gain a more detailed insight into the interactions between the compounds and the enzyme. The hydrogen bonds and hydrophobic contacts were characterized for the complexes. Through structural alignment, the catalytic residues Cys1013 and His1083 were identified in the N-terminal region of the nsP2 protease. The absolute binding free energies were estimated by the linear interaction energy approach and compared with the binding affinities predicted with docking. The resu...

show abstract

Molecular insight into the specific binding of ADP-ribose to the nsP3 macro domains of chikungunya and venezuelan equine encephalitis viruses: Molecular dynamics simulations and free energy calculations

Cited by 49 publications

References 40 publications

Hypervariable Domain of Nonstructural Protein nsP3 of Venezuelan Equine Encephalitis Virus Determines Cell-Specific Mode of Virus Replication

Hypervariable Domain of Nonstructural Protein nsP3 of Venezuelan Equine Encephalitis Virus Determines Cell-Specific Mode of Virus Replication

The FHA and BRCT domains recognize ADP-ribosylation during DNA damage response

Identification of chikungunya virus nsP2 protease inhibitors using structure-base approaches

Contact Info

Product

Resources

About