高雄醫學大學圖書館 |

Structural Dynamic Insights into Coronavirus Spike Conformational States, Receptor Activation, and Vaccines /

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Structural Dynamic Insights into Coronavirus Spike Conformational States, Receptor Activation, and Vaccines // Chengbo Chen.
Author:	Chen, Chengbo,
Description:	1 electronic resource (169 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-03, Section: B.
基督教聖經之智慧書導讀 :	Viruses in the Sarbecovirus subgenus have given rise to two highly transmissible coronaviruses in recent human history: severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2. These viruses enter human cells through the binding between viral spike (S) glycoprotein and a common human angiotensin-converting enzyme 2 (hACE2) receptor. However, they exhibit differences in interactions with hACE2 as well as in proteolytic processing of S that trigger the fusion machinery. Identifying the molecular basis of how these differences impact S activation as well as the effects of mutations found in novel SARS-CoV-2 variants of concern (VOCs) is key to understand S function and viral pathogenesis phenotypes.The hypothesis I am testing is that differences in structural and conformational dynamics in SARS-CoV and SARS-CoV-2 spike trimers influence their ability to bind and be activated by the hACE2 receptor. To probe the structural and dynamic differences among SARS-CoV, SARS-CoV-2 and VOCs that exhibit different transmissibility, we perform hydrogen/deuterium-exchange mass spectrometry (HDX-MS), which measures protein dynamics under native conditions. HDX-MS reveals differences in spike dynamics at various levels, which will be discussed in three chapters with specific focus.In Chapter 2, HDX-MS reveals differences in dynamics of unbound S, featuring the D614G mutation-induced S conformational switch to open states and S stability. This open conformation, involving the receptor-binding domain (RBD) in the up conformation, is impaired when its N-glycosylation at position 343 is knocked down, indicating that RBD dynamics are influenced by glycan-facilitated neighboring N-terminal domain (NTD)-RBD crosstalk. In Chapter 3, we discover that hACE2 binding leads to more prominent dynamic behaviors reflecting hACE2-induced S activation. Notable differences in transduction of allosteric changes are observed, extending from the RBD to regions proximal to proteolytic cleavage sites, suggesting that the highly dynamic fusion peptide region in SARS-CoV-2 S can confer an advantage in fusion. In Chapter 4, we investigate both S conformational dynamics and local structural ordering with a focus on mosaic spike heterotrimers mimicking possible antigenic assemblies from bivalent mRNA vaccination. Both trimer stability and antigenicity are well-conserved in the mosaic trimer formation we study. The mosaic trimer co-expressed form Omicron and Hu-1, resembling the S sequences used in mRNA vaccines, also shows prominent dynamic changes in the fusion peptide proximal region.These results provide mechanistic insights into receptor-induced S activation. In such a highly dynamic Class I fusion machine, critical variations in amino acid sequences or post-translational modifications can significantly trigger allosteric effects through dynamic motions and interactions between domains, further impacting their transmission phenotypes and viral fitness.
Contained By:	Dissertations Abstracts International86-03B.
Subject:	Public health. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31557530
ISBN:	9798384098553

Structural Dynamic Insights into Coronavirus Spike Conformational States, Receptor Activation, and Vaccines /
Chen, Chengbo,

Structural Dynamic Insights into Coronavirus Spike Conformational States, Receptor Activation, and Vaccines /Chengbo Chen. - 1 electronic resource (169 pages)

Source: Dissertations Abstracts International, Volume: 86-03, Section: B.

Viruses in the Sarbecovirus subgenus have given rise to two highly transmissible coronaviruses in recent human history: severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2. These viruses enter human cells through the binding between viral spike (S) glycoprotein and a common human angiotensin-converting enzyme 2 (hACE2) receptor. However, they exhibit differences in interactions with hACE2 as well as in proteolytic processing of S that trigger the fusion machinery. Identifying the molecular basis of how these differences impact S activation as well as the effects of mutations found in novel SARS-CoV-2 variants of concern (VOCs) is key to understand S function and viral pathogenesis phenotypes.The hypothesis I am testing is that differences in structural and conformational dynamics in SARS-CoV and SARS-CoV-2 spike trimers influence their ability to bind and be activated by the hACE2 receptor. To probe the structural and dynamic differences among SARS-CoV, SARS-CoV-2 and VOCs that exhibit different transmissibility, we perform hydrogen/deuterium-exchange mass spectrometry (HDX-MS), which measures protein dynamics under native conditions. HDX-MS reveals differences in spike dynamics at various levels, which will be discussed in three chapters with specific focus.In Chapter 2, HDX-MS reveals differences in dynamics of unbound S, featuring the D614G mutation-induced S conformational switch to open states and S stability. This open conformation, involving the receptor-binding domain (RBD) in the up conformation, is impaired when its N-glycosylation at position 343 is knocked down, indicating that RBD dynamics are influenced by glycan-facilitated neighboring N-terminal domain (NTD)-RBD crosstalk. In Chapter 3, we discover that hACE2 binding leads to more prominent dynamic behaviors reflecting hACE2-induced S activation. Notable differences in transduction of allosteric changes are observed, extending from the RBD to regions proximal to proteolytic cleavage sites, suggesting that the highly dynamic fusion peptide region in SARS-CoV-2 S can confer an advantage in fusion. In Chapter 4, we investigate both S conformational dynamics and local structural ordering with a focus on mosaic spike heterotrimers mimicking possible antigenic assemblies from bivalent mRNA vaccination. Both trimer stability and antigenicity are well-conserved in the mosaic trimer formation we study. The mosaic trimer co-expressed form Omicron and Hu-1, resembling the S sequences used in mRNA vaccines, also shows prominent dynamic changes in the fusion peptide proximal region.These results provide mechanistic insights into receptor-induced S activation. In such a highly dynamic Class I fusion machine, critical variations in amino acid sequences or post-translational modifications can significantly trigger allosteric effects through dynamic motions and interactions between domains, further impacting their transmission phenotypes and viral fitness.

English

ISBN: 9798384098553Subjects--Topical Terms:

206087
Public health.
Subjects--Index Terms:

Allostery

Structural Dynamic Insights into Coronavirus Spike Conformational States, Receptor Activation, and Vaccines /
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520 $a Viruses in the Sarbecovirus subgenus have given rise to two highly transmissible coronaviruses in recent human history: severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2. These viruses enter human cells through the binding between viral spike (S) glycoprotein and a common human angiotensin-converting enzyme 2 (hACE2) receptor. However, they exhibit differences in interactions with hACE2 as well as in proteolytic processing of S that trigger the fusion machinery. Identifying the molecular basis of how these differences impact S activation as well as the effects of mutations found in novel SARS-CoV-2 variants of concern (VOCs) is key to understand S function and viral pathogenesis phenotypes.The hypothesis I am testing is that differences in structural and conformational dynamics in SARS-CoV and SARS-CoV-2 spike trimers influence their ability to bind and be activated by the hACE2 receptor. To probe the structural and dynamic differences among SARS-CoV, SARS-CoV-2 and VOCs that exhibit different transmissibility, we perform hydrogen/deuterium-exchange mass spectrometry (HDX-MS), which measures protein dynamics under native conditions. HDX-MS reveals differences in spike dynamics at various levels, which will be discussed in three chapters with specific focus.In Chapter 2, HDX-MS reveals differences in dynamics of unbound S, featuring the D614G mutation-induced S conformational switch to open states and S stability. This open conformation, involving the receptor-binding domain (RBD) in the up conformation, is impaired when its N-glycosylation at position 343 is knocked down, indicating that RBD dynamics are influenced by glycan-facilitated neighboring N-terminal domain (NTD)-RBD crosstalk. In Chapter 3, we discover that hACE2 binding leads to more prominent dynamic behaviors reflecting hACE2-induced S activation. Notable differences in transduction of allosteric changes are observed, extending from the RBD to regions proximal to proteolytic cleavage sites, suggesting that the highly dynamic fusion peptide region in SARS-CoV-2 S can confer an advantage in fusion. In Chapter 4, we investigate both S conformational dynamics and local structural ordering with a focus on mosaic spike heterotrimers mimicking possible antigenic assemblies from bivalent mRNA vaccination. Both trimer stability and antigenicity are well-conserved in the mosaic trimer formation we study. The mosaic trimer co-expressed form Omicron and Hu-1, resembling the S sequences used in mRNA vaccines, also shows prominent dynamic changes in the fusion peptide proximal region.These results provide mechanistic insights into receptor-induced S activation. In such a highly dynamic Class I fusion machine, critical variations in amino acid sequences or post-translational modifications can significantly trigger allosteric effects through dynamic motions and interactions between domains, further impacting their transmission phenotypes and viral fitness.
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650 4 $2 96060 $a Virology. $3 187922
650 4 $2 96060 $a Biophysics. $3 264265
653 $a Allostery
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653 $a Protein dynamics
653 $a Vaccine
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