The inherent flexibility of receptor binding domains in SARS-CoV-2 spike protein
Abstract
Spike (S) protein is the primary antigenic target for neutralization and vaccine development for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It decorates the virus surface and undergoes large motions of its receptor binding domains (RBDs) to enter the host cell. Here, we observe Down, one-Up, one-Open, and two-Up-like structures in enhanced molecular dynamics simulations, and characterize the transition pathways via inter-domain interactions. Transient salt-bridges between RBDA and RBDC and the interaction with glycan at N343B support RBDA motions from Down to one-Up. Reduced interactions between RBDA and RBDB in one-Up induce RBDB motions toward two-Up. The simulations overall agree with cryo-EM structure distributions and FRET experiments and provide hidden functional structures, namely, intermediates along Down to one-Up transition with druggable cryptic pockets as well as one-Open with a maximum exposed RBD. The inherent flexibility of S-protein thus provides essential information for antiviral drug rational design or vaccine development.
Data availability
The trajectories were computed with GENESIS 2.0 beta, open source program https:// www.r-ccs.riken.jp/labs/cbrt/ and analyzed using GENESIS 1.6.0 analysis tools https://www.r-ccs.riken.jp/labs/cbrt/download/genesis-version-1-6/ Simulation data were deposited at https://covid.molssi.org/ Data of gREST simulations from Down including models and simulation structures are availableHisham M. Dokainish, Suyong Re, Takaharu Mori, Chigusa Kobayashi, Jaewoon Jung, and Yuji Sugita (2021) MolSSI gREST_SSCR Simulation of Trimeric SARS-CoV-2 Spike Protein Starting From Down Conformation. https://doi.org/10.34974/wtbx-0r84Data of gREST_Up simulations including model and simulation structures are availableHisham M. Dokainish, Suyong Re, Takaharu Mori, Chigusa Kobayashi, Jaewoon Jung, and Yuji Sugita (2021) MolSSI gREST_SSCR Simulation of Trimeric SARS-CoV-2 Spike Protein Starting From 1Up Conformation. https://doi.org/10.34974/xn67-xk26
Article and author information
Author details
Funding
Ministry of Education, Culture, Sports, Science and Technology (FLAGSHIP 2020 project)
- Yuji Sugita
Ministry of Education, Culture, Sports, Science and Technology (19K06532)
- Takaharu Mori
RIKEN (Dynamic Structural Biology/Glycolipidologue Initiative/Biology of Intracellular Environments)
- Yuji Sugita
Ministry of Education, Culture, Sports, Science and Technology (Priority Issue on Post-K computer)
- Yuji Sugita
Ministry of Education, Culture, Sports, Science and Technology (Program for Promoting Researches on the Supercomputer Fugaku)
- Yuji Sugita
Ministry of Education, Culture, Sports, Science and Technology (JPMXP1020200101)
- Yuji Sugita
Ministry of Education, Culture, Sports, Science and Technology (JPMXP1020200201)
- Yuji Sugita
Ministry of Education, Culture, Sports, Science and Technology (19H05645)
- Yuji Sugita
Ministry of Education, Culture, Sports, Science and Technology (21H05249)
- Yuji Sugita
Ministry of Education, Culture, Sports, Science and Technology (20K15737)
- Hisham M Dokainish
Ministry of Education, Culture, Sports, Science and Technology (19K12229)
- Suyong Re
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Dokainish et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Further reading
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- Biochemistry and Chemical Biology
In healthy cells, cyclin D1 is expressed during the G1 phase of the cell cycle, where it activates CDK4 and CDK6. Its dysregulation is a well-established oncogenic driver in numerous human cancers. The cancer-related function of cyclin D1 has been primarily studied by focusing on the phosphorylation of the retinoblastoma (RB) gene product. Here, using an integrative approach combining bioinformatic analyses and biochemical experiments, we show that GTSE1 (G-Two and S phases expressed protein 1), a protein positively regulating cell cycle progression, is a previously unrecognized substrate of cyclin D1–CDK4/6 in tumor cells overexpressing cyclin D1 during G1 and subsequent phases. The phosphorylation of GTSE1 mediated by cyclin D1–CDK4/6 inhibits GTSE1 degradation, leading to high levels of GTSE1 across all cell cycle phases. Functionally, the phosphorylation of GTSE1 promotes cellular proliferation and is associated with poor prognosis within a pan-cancer cohort. Our findings provide insights into cyclin D1’s role in cell cycle control and oncogenesis beyond RB phosphorylation.
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