서브메뉴
검색
Structural Dynamic Insights into Coronavirus Spike Conformational States, Receptor Activation, and Vaccines
Structural Dynamic Insights into Coronavirus Spike Conformational States, Receptor Activation, and Vaccines
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211152808
- ISBN
- 9798384098553
- DDC
- 574.191
- 저자명
- Chen, Chengbo.
- 서명/저자
- Structural Dynamic Insights into Coronavirus Spike Conformational States, Receptor Activation, and Vaccines
- 발행사항
- [Sl] : University of Washington, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 169 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-03, Section: B.
- 주기사항
- Advisor: Lee, Kelly.
- 학위논문주기
- Thesis (Ph.D.)--University of Washington, 2024.
- 초록/해제
- 요약Viruses 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.
- 일반주제명
- Biophysics
- 일반주제명
- Virology
- 일반주제명
- Public health
- 키워드
- Allostery
- 키워드
- Fusion protein
- 키워드
- Protein dynamics
- 키워드
- Vaccine
- 기타저자
- University of Washington Medicinal Chemistry
- 기본자료저록
- Dissertations Abstracts International. 86-03B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
008250123s2024 us c eng d■001000017163910
■00520250211152808
■006m o d
■007cr#unu||||||||
■020 ▼a9798384098553
■035 ▼a(MiAaPQ)AAI31557530
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a574.191
■1001 ▼aChen, Chengbo.
■24510▼aStructural Dynamic Insights into Coronavirus Spike Conformational States, Receptor Activation, and Vaccines
■260 ▼a[Sl]▼bUniversity of Washington▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a169 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-03, Section: B.
■500 ▼aAdvisor: Lee, Kelly.
■5021 ▼aThesis (Ph.D.)--University of Washington, 2024.
■520 ▼aViruses 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.
■590 ▼aSchool code: 0250.
■650 4▼aBiophysics
■650 4▼aVirology
■650 4▼aPublic health
■653 ▼aAllostery
■653 ▼aFusion protein
■653 ▼aProtein dynamics
■653 ▼aVaccine
■653 ▼aReceptor-binding domain
■690 ▼a0786
■690 ▼a0720
■690 ▼a0573
■71020▼aUniversity of Washington▼bMedicinal Chemistry.
■7730 ▼tDissertations Abstracts International▼g86-03B.
■790 ▼a0250
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17163910▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
