The Crystal Structures of Chikungunya and Venezuelan Equine Encephalitis Virus nsP3 Macro Domains Define a Conserved Adenosine Binding Pocket

Malet, Hélène; Coutard, Bruno; Jamal, S.; Dutartre, Hélène; Papageorgiou, Nicolas; Neuvonen, Maarit; Ahola, Tero; Forrester, Naomi L.; Gould, Ernest A.; Lafitte, Daniel; Ferrón, François; Lescar, Julien; Gorbalenya, Alexander E.; Lamballerie, Xavier de; Canard, Bruno

doi:10.1128/jvi.00189-09

Cited by 203 publications

(293 citation statements)

References 51 publications

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“…It was noteworthy that the good scoring phytochemicals bind to the conserved aspartic acid (D10).Some phytochemicals used hydrogen bond to interact with D10 while others had non-bonded interactions. This single aspartic acid, conserved through all macro domains is responsible for the specific binding of the adenine base (Malet et al, 2009).The affinity between the receptor and the substrate may get disturbed due to this strong binding. The DockScore of the ligands showed that the receptor-ligand interaction energy and the ligand internal energy were in the most favorable range.…”

Section: Resultsmentioning

confidence: 99%

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Towards the Identification of Novel Phytochemical Leads as Macrodomain Inhibitors of Chikungunya Virus Using Molecular Docking Approach

2017

J App Pharma Sci

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The outbreak of Chikungunya fever worldwide has raised a threat to human health and an economic burden on the affected countries. Currently, there is no cure for Chikungunya. The computational methods assist in identifying the drug leads for the target. This work reports the potential phytochemical inhibitors against a unique macro domain present in the conserved N-terminal region of Non-structural protein nsP3 of Chikungunya virus. Macro domain contributes a lot to viral fusion and replication. The shape based docking protocol was applied to predict the ligand conformations and their relative orientations with 2-ADP Ribose binding site of the target. The phytochemicals showed favorable bonded and non-bonded interactions with crucial amino acids. The binding affinity of the ligands to the target structure was estimated with six wellknown scoring functions. An all-atom molecular dynamics simulation was performed for the macro domain in apo form and the complex with the best scoring ligand to study the stability and the conformational flexibility of the complexes. Based on the multiple scoring functions, drug-like properties, amino acid interactions and molecular dynamics studies, it is believed that the phytochemicals screened may well compete with the substrate. This is turn can inhibit the function of macro domain, eventually the loss of virulence of chikungunya virus. The work also gives a room for designing novel drugs using chemoinformatics, based on the structures of phytochemical leads reported in this study.

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Section: Resultsmentioning

confidence: 99%

“…The crystal structure of Chikungunya virus nsP3 macro domain that defines a conserved adenosine binding pocket (3GPO) was considered as the target of the study (Malet et al, 2009). It was retrieved from the Protein Data Bank (Berman et al, 2000).…”

Section: Methodsmentioning

confidence: 99%

Towards the Identification of Novel Phytochemical Leads as Macrodomain Inhibitors of Chikungunya Virus Using Molecular Docking Approach

2017

J App Pharma Sci

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“…The ribose and pyrophosphate group fit well into the pocket formed by the two loop regions (G314-N316 and G223-G224). As a result, the macro domain specifically recognizes the terminal ADP-ribose moiety of the poly-ADP-ribose chain [21][22][23] (Fig. S10B).…”

Section: Comparison With the Adp-ribose Binding Modes Of Other Recognmentioning

confidence: 99%

Structural insight into the interaction of ADP‐ribose with the PARP WWE domains

Tsuda

Takahashi

et al. 2012

FEBS Letters

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a b s t r a c tThe WWE domain is often identified in proteins associated with ubiquitination or poly-ADP-ribosylation. Structural information about WWE domains has been obtained for the ubiquitination-related proteins, such as Deltex and RNF146, but not yet for the poly-ADP-ribose polymerases (PARPs). Here we determined the solution structures of the WWE domains from PARP11 and PARP14, and compared them with that of the RNF146 WWE domain. NMR perturbation experiments revealed the specific differences in their ADP-ribose recognition modes that correlated with their individual biological activities. The present structural information sheds light on the ADP-ribose recognition modes by the PARP WWE domains.

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“…We recently determined the crystal structures of macro domain from the Chikungunya virus (CHIKV) and the Venezuelan Equine Encephalitis virus (VEEV) at 1.65 A and 2.30 A resolution respectively by single crystal X-ray diffraction. These macro domains are active as adenosine di-phosphoribose 1 00 -phosphate phosphatases [16]. Despite significant effort good quality single crystals of the MAYV nsP3 macro domain were not available whereas crystallization trials resulted in reproducible microcrystalline samples, mainly needles as shown in Fig.…”

Section: Introductionmentioning

confidence: 99%

Preliminary insights into the non structural protein 3 macro domain of the Mayaro virus by powder diffraction

Papageorgiou¹,

Watier

Saunders

et al. 2010

Zeitschrift Für Kristallographie

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Abstract. We present preliminary structural results of the non-structural protein 3 (nsP3) macro domain from the Mayaro virus (MAYV), an emerging virus of South American tropic regions, by means of synchrotron X-ray powder diffraction. Indexing of the diffraction patterns indicate a trigonal/hexagonal lattice (a ¼ 61:60 A, c ¼ 94:61 A), analogous to the known lattice of the sequence homologous nsP3 macro domain from the Chikungunia virus (CHIKV), though MAYV must have looser molecular packing: the cell dimensions of MAYV are significantly altered in comparison to CHIKV and the unit cell comprises 6 molecules and 58% solvent. The results are discussed in terms of their methodological and biological importance.

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The Crystal Structures of Chikungunya and Venezuelan Equine Encephalitis Virus nsP3 Macro Domains Define a Conserved Adenosine Binding Pocket

Abstract: Macro domains (also called"

Cited by 203 publications

References 51 publications

Towards the Identification of Novel Phytochemical Leads as Macrodomain Inhibitors of Chikungunya Virus Using Molecular Docking Approach

Towards the Identification of Novel Phytochemical Leads as Macrodomain Inhibitors of Chikungunya Virus Using Molecular Docking Approach

Structural insight into the interaction of ADP‐ribose with the PARP WWE domains

Preliminary insights into the non structural protein 3 macro domain of the Mayaro virus by powder diffraction

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