Effect of T68A/N126Y mutations on the conformational and ligand binding landscape of Coxsackievirus B3 3C protease

Bhakat, Soumendranath

doi:10.1039/c5mb00262a

Cited by 6 publications

(3 citation statements)

References 30 publications

(38 reference statements)

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“…This virus belongs to the picornaviridae family and consists of a positive single-stranded RNA that exhibits frequent variation (Lum et al, 1998 ; Ho, 2000 ). Previous research on the relationship between viral genetic sequences and virulence mainly focused on two proteins: VP1 and 3D (Parks et al, 1989 ; Meng and Kwang, 2014 ; Zhang et al, 2014 ; Bhakat, 2015 ; Yuan et al, 2015 ). Some reports showed that a single mutation of VP1 or 3D would lead to great changes in the severity of symptoms.…”

Section: Discussionmentioning

confidence: 99%

A Novel Enterovirus 71 (EV71) Virulence Determinant: The 69th Residue of 3C Protease Modulates Pathogenicity

Yue

Zhang

et al. 2017

Front. Cell. Infect. Microbiol.

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Human enterovirus type 71 (EV71), the major causative agent of hand-foot-and-mouth disease, has been known to cause fatal neurological complications. Unfortunately, the reason for neurological complications that have been seen in fatal cases of the disease and the relationship between EV71 virulence and viral genetic sequences remains largely undefined. The 3C protease (3Cpro) of EV71 plays an irreplaceable role in segmenting the precursor polyprotein during viral replication, and intervening with host life activity during viral infection. In this study, for the first time, the 69th residue of 3C protease has been identified as a novel virulence determinant of EV71. The recombinant virus with single point variation, in the 69th of 3Cpro, exhibited obvious decline in replication, and virulence. We further determined the crystal structure of 3C N69D at 1.39 Ǻ resolution and found that conformation of 3C N69D demonstrated significant changes compared with a normal 3C protein, in the substrate-binding site and catalytic active site. Strikingly, one of the switch loops, essential in fixing substrates, adopts an open conformation in the 3C N69D-rupintrivir complex. Consistent with this apparent structural disruption, the catalytic activity of 3C N69D decreased sharply for host derived and viral derived substrates, detected for both in vitro and in vivo. Interestingly, in addition to EV71, Asp69 was also found in 3C proteases of other virus strains, such as CAV16, and was conserved in nearly all C type human rhinovirus. Overall, we identified a natural virulence determinant of 3C protease and revealed the mechanism of attenuated virulence is mediated by N69D substitution. Our data provides new insight into the enzymatic mechanism of a subdued 3C protease and suggests a theoretical basis for virulence determinantion of picornaviridae.

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Section: Discussionmentioning

confidence: 99%

A Novel Enterovirus 71 (EV71) Virulence Determinant: The 69th Residue of 3C Protease Modulates Pathogenicity

Yue

Zhang

et al. 2017

Front. Cell. Infect. Microbiol.

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“…Moreover, fluctuation in the Rg value of the mutated protease during the simulation period also indicates that, at some places, the structure became more rigid, while at other places it showed less compactness. Overall, the change in the Rg value of the mutated structure in comparison to the wild-type structure was in the line of mutation-based conformational distortion hypothesis, which ultimately results in a lose grip on the drug molecule [14].…”

Section: Effect Of the M46i Mutation On Conformational Compactnessmentioning

confidence: 65%

Drug Resistance Mechanism of M46I-Mutation-Induced Saquinavir Resistance in HIV-1 Protease Using Molecular Dynamics Simulation and Binding Energy Calculation

Rana

Singh

Shuaib

et al. 2022

Viruses

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Drug-resistance-associated mutation in essential proteins of the viral life cycle is a major concern in anti-retroviral therapy. M46I, a non-active site mutation in HIV-1 protease has been clinically associated with saquinavir resistance in HIV patients. A 100 ns molecular dynamics (MD) simulation and MM-PBSA calculations were performed to study the molecular mechanism of M46I-mutation-based saquinavir resistance. In order to acquire deeper insight into the drug-resistance mechanism, the flap curling, closed/semi-open/open conformations, and active site compactness were studied. The M46I mutation significantly affects the energetics and conformational stability of HIV-1 protease in terms of RMSD, RMSF, Rg, SASA, and hydrogen formation potential. This mutation significantly decreased van der Waals interaction and binding free energy (∆G) in the M46I–saquinavir complex and induced inward flap curling and a wider opening of the flaps for most of the MD simulation period. The predominant open conformation was reduced, but inward flap curling/active site compactness was increased in the presence of saquinavir in M46I HIV-1 protease. In conclusion, the M46I mutation induced structural dynamics changes that weaken the protease grip on saquinavir without distorting the active site of the protein. The produced information may be utilized for the discovery of inhibitor(s) against drug-resistant HIV-1 protease.

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“…Molecular interaction studies are important for understanding the mechanism of biological regulation at the molecular level and as such also provides a theoretical basis for drug design and discovery [49,50]. Hydrogen and hydrophobic interactions are key players in stabilizing energetically favored ligands, in an open conformational environment of protein structures [29].…”

Section: Protein-ligand Interactionmentioning

confidence: 99%

Molecular Informatics of Trypanothione Reductase of Leishmania major Reveals Novel Chromen-2-One Analogues as Potential Leishmanicides

Kwofie¹,

Kwarko²,

Broni³

et al. 2022

Leishmaniasis - General Aspects of a Stigmatized Disease

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Trypanothione reductase (TR), a flavoprotein oxidoreductase is an important therapeutic target for leishmaniasis. Ligand-based pharmacophore modelling and molecular docking were used to predict selective inhibitors against TR. Homology modelling was employed to generate a three-dimensional structure of Leishmania major trypanothione reductase (LmTR). A pharmacophore model used to screen a natural compound library generated 42 hits, which were docked against the LmTR protein. Compounds with lower binding energies were evaluated via in silico pharmacological profiling and bioactivity. Four compounds emerged as potential leads comprising Karatavicinol (7-[(2E,6E,10S)-10,11-dihydroxy-3,7,11-trimethyldodeca-2,6-dienoxy]chromen-2-one), Marmin (7-[(E,6R)-6,7-dihydroxy-3,7-dimethyloct-2-enoxy]chromen-2-one), Colladonin (7-[[(4aS)-6-hydroxy-5,5,8a-trimethyl-2-methylidene-3,4,4a,6,7,8-hexahydro-1H-naphthalen-1-yl]methoxy]chromen-2-one), and Pectachol (7-[(6-hydroxy-5,5,8a-trimethyl-2-methylidene-3,4,4a,6,7,8-hexahydro-1H-naphthalen-1-yl)methoxy]-6,8-dimethoxychromen-2-one) with good binding energies of −9.4, −9.3, 8.8, and −8.5 kcal/mol, respectively. These compounds bound effectively to the FAD domain of the protein with some critical residues including Asp35, Thr51, Lys61, Tyr198, and Asp327. Furthermore, molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area (MMPBSA) computations corroborated their strong binding. The compounds were also predicted to possess anti-leishmanial activity. The molecules serves as templates for the design of potential drug candidates and can be evaluated in vitro with optimistic results in producing plausible attenuating infectivity in macrophages.

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Effect of T68A/N126Y mutations on the conformational and ligand binding landscape of Coxsackievirus B3 3C protease

Cited by 6 publications

References 30 publications

A Novel Enterovirus 71 (EV71) Virulence Determinant: The 69th Residue of 3C Protease Modulates Pathogenicity

A Novel Enterovirus 71 (EV71) Virulence Determinant: The 69th Residue of 3C Protease Modulates Pathogenicity

Drug Resistance Mechanism of M46I-Mutation-Induced Saquinavir Resistance in HIV-1 Protease Using Molecular Dynamics Simulation and Binding Energy Calculation

Molecular Informatics of Trypanothione Reductase of Leishmania major Reveals Novel Chromen-2-One Analogues as Potential Leishmanicides

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