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Exploring Molecular Glues for 14-3-3 Protein-Protein Interactions
Exploring Molecular Glues for 14-3-3 Protein-Protein Interactions
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260202104810
- ISBN
- 9798293856060
- DDC
- 574
- 저자명
- Virta, Johanna.
- 서명/저자
- Exploring Molecular Glues for 14-3-3 Protein-Protein Interactions
- 발행사항
- [Sl] : University of California, San Francisco, 2025
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2025
- 형태사항
- 322 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 87-03, Section: B.
- 주기사항
- Advisor: Arkin, Michelle R.
- 학위논문주기
- Thesis (Ph.D.)--University of California, San Francisco, 2025.
- 초록/해제
- 요약14-3-3 regulates the activity of thousands of client proteins in various biological pathways through physical occlusion, structural conformations, and scaffolding protein-protein interactions (PPIs). Utilizing the role of 14-3-3 to regulate client proteins, the Arkin lab has developed molecule glues (MGs) that stabilize native 14-3-3/client interactions, harnessing the negative regulatory interactions to "turn off" client proteins' functions in disease. By targeting PPIs as opposed to singular proteins, selectivity can be enhanced through selective MGs that bind the unique composite interfaces for a PPI of interest. This also allows for unstructured proteins/regions that were previously difficult to target to gain new induced binding pockets for modulators for the development of novel therapeutics. The work presented in this dissertation showcases the work on exploring MGs for various 14-3-3/client interactions, with focus on the 14-3-3/ERα and 14-3-3/CRAF complexes. These client proteins represent crucial targets in cancer (ERα and CRAF) and in developmental RASopathies (CRAF) that have distinct functions and binding modes to 14-3-3. Capitalizing on the differences allowed for the development of selective MGs and assays to characterize the effects of stabilizing these 14-3-3/client interactions. Work along each step of the drug discovery and development for 14-3-3/client MGs is presented in this dissertation: screening and validation of stabilizing fragments, optimization of fragment hits into selective MGs, and characterization of cell-active MGs. The lessons learned in each chapter provide insight into 14- 3-3 biology in the regulation of transcription factors (ERα) and kinases (CRAF) as well as serving as building blocks to expand stabilization to other native or neomorphic PPIs.
- 일반주제명
- Biochemistry
- 일반주제명
- Chemistry
- 일반주제명
- Translation studies
- 일반주제명
- Oncology
- 일반주제명
- Molecular biology
- 키워드
- 14-3-3
- 키워드
- Cancer
- 키워드
- Molecular glues
- 키워드
- RASopathies
- 기타저자
- University of California, San Francisco Chemistry and Chemical Biology
- 기본자료저록
- Dissertations Abstracts International. 87-03B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520260202104810
■006m o d
■007cr#unu||||||||
■020 ▼a9798293856060
■035 ▼a(MiAaPQ)AAI32166994
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a574
■1001 ▼aVirta, Johanna.▼0(orcid)0000-0001-9893-5565
■24510▼aExploring Molecular Glues for 14-3-3 Protein-Protein Interactions
■260 ▼a[Sl]▼bUniversity of California, San Francisco▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a322 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 87-03, Section: B.
■500 ▼aAdvisor: Arkin, Michelle R.
■5021 ▼aThesis (Ph.D.)--University of California, San Francisco, 2025.
■520 ▼a14-3-3 regulates the activity of thousands of client proteins in various biological pathways through physical occlusion, structural conformations, and scaffolding protein-protein interactions (PPIs). Utilizing the role of 14-3-3 to regulate client proteins, the Arkin lab has developed molecule glues (MGs) that stabilize native 14-3-3/client interactions, harnessing the negative regulatory interactions to "turn off" client proteins' functions in disease. By targeting PPIs as opposed to singular proteins, selectivity can be enhanced through selective MGs that bind the unique composite interfaces for a PPI of interest. This also allows for unstructured proteins/regions that were previously difficult to target to gain new induced binding pockets for modulators for the development of novel therapeutics. The work presented in this dissertation showcases the work on exploring MGs for various 14-3-3/client interactions, with focus on the 14-3-3/ERα and 14-3-3/CRAF complexes. These client proteins represent crucial targets in cancer (ERα and CRAF) and in developmental RASopathies (CRAF) that have distinct functions and binding modes to 14-3-3. Capitalizing on the differences allowed for the development of selective MGs and assays to characterize the effects of stabilizing these 14-3-3/client interactions. Work along each step of the drug discovery and development for 14-3-3/client MGs is presented in this dissertation: screening and validation of stabilizing fragments, optimization of fragment hits into selective MGs, and characterization of cell-active MGs. The lessons learned in each chapter provide insight into 14- 3-3 biology in the regulation of transcription factors (ERα) and kinases (CRAF) as well as serving as building blocks to expand stabilization to other native or neomorphic PPIs.
■590 ▼aSchool code: 0034.
■650 4▼aBiochemistry
■650 4▼aChemistry
■650 4▼aTranslation studies
■650 4▼aOncology
■650 4▼aMolecular biology
■653 ▼a14-3-3
■653 ▼aCancer
■653 ▼aInduced proximity
■653 ▼aMolecular glues
■653 ▼aProtein-protein interactions
■653 ▼aRASopathies
■690 ▼a0487
■690 ▼a0485
■690 ▼a0213
■690 ▼a0992
■690 ▼a0307
■71020▼aUniversity of California, San Francisco▼bChemistry and Chemical Biology.
■7730 ▼tDissertations Abstracts International▼g87-03B.
■790 ▼a0034
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17358926▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
