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The Application of Chemoproteomic Techniques to Investigate Protein-Protein Interactions Including but Not Limited to Degradation, Inhibition, and Binding
The Application of Chemoproteomic Techniques to Investigate Protein-Protein Interactions Including but Not Limited to Degradation, Inhibition, and Binding
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260202103558
- ISBN
- 9798288864674
- DDC
- 540
- 서명/저자
- The Application of Chemoproteomic Techniques to Investigate Protein-Protein Interactions Including but Not Limited to Degradation, Inhibition, and Binding
- 발행사항
- [Sl] : University of California, Berkeley, 2025
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2025
- 형태사항
- 200 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 87-01, Section: B.
- 주기사항
- Includes supplementary digital materials.
- 주기사항
- Advisor: Nomura, Daniel K.;Doudna, Jennifer A.
- 학위논문주기
- Thesis (Ph.D.)--University of California, Berkeley, 2025.
- 초록/해제
- 요약Small molecules capable of modulating protein fate and function have expanded the scope of chemical biology. Covalent chemoproteomic strategies offer a means to systematically identify ligandable sites, develop proximity-based modalities, and interrogate protein-level mechanisms with proteome-wide resolution. This dissertation describes three efforts to apply covalent chemistry, structural constraint, and proteomics to probe and perturb protein behavior.First, the impact of stereochemistry on molecular recognition is examined through the synthesis and profiling of all four stereoisomers of vicinal difluorides. These conformationally biased motifs were incorporated into chemical probes and shown to engage distinct protein targets in a stereoselective manner, including TXNRD2, highlighting the influence of geometric constraints on target engagement.Second, chemoproteomic screening identified a covalent ligand for the E3 ligase KLHL20, which was used to develop heterobifunctional degraders. While degradation of the intended target was observed, the responsible ligase could not be conclusively identified, underscoring challenges in mechanistic validation of proximity-based degraders. Third, proximity labelling proteomics was used to characterize the intracellular trafficking of Cas9 ribonucleoprotein complexes delivered by distinct modalities. Time- and delivery-dependent changes in the Cas9 interactome revealed differences in nuclear import and degradation, providing insight into how delivery strategy shapes pharmacokinetic behaviour. Together, these studies integrate covalent ligand discovery, stereochemical design, and proteomic analysis to expand the toolkit for controlling and investigating protein function, and to inform the rational development of proximity-based therapeutic strategies.
- 일반주제명
- Chemistry
- 일반주제명
- Biochemistry
- 일반주제명
- Biology
- 일반주제명
- Pharmacology
- 키워드
- CRISPR-Cas9
- 키워드
- PROTAC
- 기타저자
- University of California, Berkeley Chemistry
- 기본자료저록
- Dissertations Abstracts International. 87-01B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■007cr#unu||||||||
■020 ▼a9798288864674
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■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a540
■1001 ▼aThomas, Vienna C. J. X. M.
■24510▼aThe Application of Chemoproteomic Techniques to Investigate Protein-Protein Interactions Including but Not Limited to Degradation, Inhibition, and Binding
■260 ▼a[Sl]▼bUniversity of California, Berkeley▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a200 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 87-01, Section: B.
■500 ▼aIncludes supplementary digital materials.
■500 ▼aAdvisor: Nomura, Daniel K.;Doudna, Jennifer A.
■5021 ▼aThesis (Ph.D.)--University of California, Berkeley, 2025.
■520 ▼aSmall molecules capable of modulating protein fate and function have expanded the scope of chemical biology. Covalent chemoproteomic strategies offer a means to systematically identify ligandable sites, develop proximity-based modalities, and interrogate protein-level mechanisms with proteome-wide resolution. This dissertation describes three efforts to apply covalent chemistry, structural constraint, and proteomics to probe and perturb protein behavior.First, the impact of stereochemistry on molecular recognition is examined through the synthesis and profiling of all four stereoisomers of vicinal difluorides. These conformationally biased motifs were incorporated into chemical probes and shown to engage distinct protein targets in a stereoselective manner, including TXNRD2, highlighting the influence of geometric constraints on target engagement.Second, chemoproteomic screening identified a covalent ligand for the E3 ligase KLHL20, which was used to develop heterobifunctional degraders. While degradation of the intended target was observed, the responsible ligase could not be conclusively identified, underscoring challenges in mechanistic validation of proximity-based degraders. Third, proximity labelling proteomics was used to characterize the intracellular trafficking of Cas9 ribonucleoprotein complexes delivered by distinct modalities. Time- and delivery-dependent changes in the Cas9 interactome revealed differences in nuclear import and degradation, providing insight into how delivery strategy shapes pharmacokinetic behaviour. Together, these studies integrate covalent ligand discovery, stereochemical design, and proteomic analysis to expand the toolkit for controlling and investigating protein function, and to inform the rational development of proximity-based therapeutic strategies.
■590 ▼aSchool code: 0028.
■650 4▼aChemistry
■650 4▼aBiochemistry
■650 4▼aBiology
■650 4▼aPharmacology
■653 ▼aCRISPR-Cas9
■653 ▼aInduced proximity
■653 ▼aPROTAC
■653 ▼aProtein-protein interactions
■653 ▼aTargeted protein degradation
■653 ▼aTMT-based quantitative proteomics
■690 ▼a0485
■690 ▼a0487
■690 ▼a0306
■690 ▼a0419
■71020▼aUniversity of California, Berkeley▼bChemistry.
■7730 ▼tDissertations Abstracts International▼g87-01B.
■790 ▼a0028
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17357770▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
