Structural insight into the recognition of S-adenosyl-L-homocysteine and sinefungin in SARS-CoV-2 Nsp16/Nsp10 RNA cap 2′-O-Methyltransferase

Mahalapbutr, Panupong; Kongtaworn, Napat; Rungrotmongkol, Thanyada

doi:10.1016/j.csbj.2020.09.032

Cited by 32 publications

(18 citation statements)

References 50 publications

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“…Likewise, in vitro studies showed that the extra addition of the Nsp10 protein enhances the weak Nsp14 ExoN activity (Baddock et al, 2020;Bouvet et al, 2012). In the case of Nsp16, a strong interaction of Nsp16 with Nsp10 was shown to trigger its 2 0 -O-methyltransferase (2 0 -O-MTase) activity (Bouvet et al, 2010;Imbert et al, 2008;Lin et al, 2020;Mahalapbutr et al, 2020). The direct interactions of both Nsp10-Nsp14 and Nsp10-Nsp16 were also validated by CoPIC (Figures 3 and S4), implying the importance of Nsp10 in two distinct regulatory mechanisms (Nsp14-ExoN and Nsp16-2 0 -O-MTase).…”

Section: Analysis Of the Interaction Hub Concentrated On Nsp12-nsp16mentioning

confidence: 99%

Compartmentalization-aided interaction screening reveals extensive high-order complexes within the SARS-CoV-2 proteome

Xu¹,

Pei²,

Liu³

et al. 2021

Cell Reports

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Bearing a relatively large single-stranded RNA genome in nature, SARS-CoV-2 utilizes sophisticated replication/transcription complexes (RTCs), mainly composed of a network of nonstructural proteins and nucleocapsid protein, to establish efficient infection. Here, we develop an innovative interaction screening strategy based on phase separation in cellulo , namely co mpartmentalization of p rotein-protein i nteractions in c ells (CoPIC). Utilizing CoPIC screening, we map the interaction network among RTC-related viral proteins. We identify a total of 47 binary interactions among 14 proteins governing replication, discontinuous transcription, and translation of coronaviruses. Further exploration via CoPIC leads to the discovery of extensive ternary complexes composed of these components, which infer potential higher-order complexes. Taken together, our results present an efficient, and robust interaction screening strategy, and indicate the existence of a complex interaction network among RTC-related factors, thus opening up opportunities to understand SARS-CoV-2 biology and develop therapeutic interventions for COVID-19.

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Section: Analysis Of the Interaction Hub Concentrated On Nsp12-nsp16mentioning

confidence: 99%

Compartmentalization-aided interaction screening reveals extensive high-order complexes within the SARS-CoV-2 proteome

Xu¹,

Pei²,

Liu³

et al. 2021

Cell Reports

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“…The four systems were performed with two rounds of energy minimization as reported previously by a combination of steepest descent and conjugate gradient minimizations ( Lu et al, 2019b ; Mahalapbutr et al, 2020 ; Shi et al, 2020 ; Vatansever et al, 2020 ; Wang et al, 2021a ; Lu et al, 2021b ). Afterwards, 500 ps heating, and 1,000 ps equilibration at 300 K under the NVT ensemble were performed with all heavy atoms of protein-ligand complexes fixed by a 10 kcal/(mol Å 2 ) force constant.…”

Section: Methodsmentioning

confidence: 99%

Deciphering the Mechanism of Gilteritinib Overcoming Lorlatinib Resistance to the Double Mutant I1171N/F1174I in Anaplastic Lymphoma Kinase

Liang

Wang

et al. 2021

Front. Cell Dev. Biol.

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Anaplastic lymphoma kinase (ALK) is validated as a therapeutic molecular target in multiple malignancies, such as non-small cell lung cancer (NSCLC). However, the feasibility of targeted therapies exerted by ALK inhibitors is inevitably hindered owing to drug resistance. The emergence of clinically acquired drug mutations has become a major challenge to targeted therapies and personalized medicines. Thus, elucidating the mechanism of resistance to ALK inhibitors is helpful for providing new therapeutic strategies for the design of next-generation drug. Here, we used molecular docking and multiple molecular dynamics simulations combined with correlated and energetical analyses to explore the mechanism of how gilteritinib overcomes lorlatinib resistance to the double mutant ALK I1171N/F1174I. We found that the conformational dynamics of the ALK kinase domain was reduced by the double mutations I1171N/F1174I. Moreover, energetical and structural analyses implied that the double mutations largely disturbed the conserved hydrogen bonding interactions from the hinge residues Glu1197 and Met1199 in the lorlatinib-bound state, whereas they had no discernible adverse impact on the binding affinity and stability of gilteritinib-bound state. These discrepancies created the capacity of the double mutant ALK I1171N/F1174I to confer drug resistance to lorlatinib. Our result anticipates to provide a mechanistic insight into the mechanism of drug resistance induced by ALK I1171N/F1174I that are resistant to lorlatinib treatment in NSCLC.

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“…High conservation of the MTase site between different nidoviruses supports the idea that the catalytic site is targeted with compounds such as sinefongin [ 115 ]. Other drugs were also proposed as MTase inhibitor candidates after in silico analysis of SARS-CoV-2 NSP16 [ 117 , 118 ]. Moreover, interaction between SARS-CoV-2 NSP10 and NSP16 occurs between Val42 and Leu45 of NSP10 and two hydrophobic pockets found in NSP16.…”

Section: Structure and Function Of The Sars-cov-2 Rna Polymerase: Thementioning

confidence: 99%

Analysis of the SARS-CoV-2-host protein interaction network reveals new biology and drug candidates: focus on the spike surface glycoprotein and RNA polymerase

Sokullu

Pinard

Gauthier

et al. 2021

Expert Opinion on Drug Discovery

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Introduction : The COVID-19 pandemic originated from the emergence of anovel coronavirus, SARS-CoV-2, which has been intensively studied since its discovery in order to generate the knowledge necessary to accelerate the development of vaccines and antivirals. Of note, many researchers believe there is great potential in systematically identifying host interactors of viral factors already targeted by existing drugs. Areas Covered : Herein, the authors discuss in detail the only available large-scale systematic study of the SARS-CoV-2-host protein–protein interaction network. More specifically, the authors review the literature on two key SARS-CoV-2 drug targets, the Spike surface glycoprotein, and the RNA polymerase. The authors also provide the reader with their expert opinion and future perspectives. Expert opinion : Interactions made by viral proteins with host factors reveal key functions that are likely usurped by the virus and, as aconsequence, points to known drugs that can be repurposed to fight viral infection and collateral damages that can exacerbate various disease conditions in COVID-19.

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Structural insight into the recognition of S-adenosyl-L-homocysteine and sinefungin in SARS-CoV-2 Nsp16/Nsp10 RNA cap 2′-O-Methyltransferase

Abstract: Graphical abstract

Cited by 32 publications

References 50 publications

Compartmentalization-aided interaction screening reveals extensive high-order complexes within the SARS-CoV-2 proteome

Compartmentalization-aided interaction screening reveals extensive high-order complexes within the SARS-CoV-2 proteome

Deciphering the Mechanism of Gilteritinib Overcoming Lorlatinib Resistance to the Double Mutant I1171N/F1174I in Anaplastic Lymphoma Kinase

Analysis of the SARS-CoV-2-host protein interaction network reveals new biology and drug candidates: focus on the spike surface glycoprotein and RNA polymerase

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