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On the Allosteric Mechanisms of Paradoxical Activation by RAF Inhibitors
On the Allosteric Mechanisms of Paradoxical Activation by RAF Inhibitors
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211151142
- ISBN
- 9798382726588
- DDC
- 574.191
- 서명/저자
- On the Allosteric Mechanisms of Paradoxical Activation by RAF Inhibitors
- 발행사항
- [Sl] : University of Minnesota, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 169 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 85-11, Section: B.
- 주기사항
- Advisor: Levinson, Nicholas M.
- 학위논문주기
- Thesis (Ph.D.)--University of Minnesota, 2024.
- 초록/해제
- 요약The type II class of RAF inhibitors currently in clinical trials paradoxically activate BRAF at sub-saturating concentrations. Activation is mediated by induction of BRAF dimers, but why activation rather than inhibition occurs remains unclear. Using biophysical methods tracking BRAF dimerization and conformation, we built an allosteric model of inhibitor-induced dimerization that resolves the allosteric contributions of inhibitor binding to the two active sites of the dimer, revealing key differences between type I and type II RAF inhibitors. For type II inhibitors the allosteric coupling between inhibitor binding and BRAF dimerization is distributed asymmetrically across the two dimer binding sites, with binding to the first site dominating the allostery. This asymmetry results in efficient and selective induction of dimers with one inhibited and one catalytically active subunit. Our allosteric models quantitatively account for paradoxical activation data measured for 11 RAF inhibitors. Unlike type II inhibitors, type I inhibitors lack allosteric asymmetry and do not activate BRAF homodimers. Finally, 19F-NMR data reveal that BRAF homodimers are dynamically asymmetric, with only one of the subunits locked in the active αC-in state. This provides a structural mechanism for how binding of only a single αC-in inhibitor molecule can induce potent BRAF dimerization and activation.
- 일반주제명
- Biophysics
- 일반주제명
- Biochemistry
- 일반주제명
- Pharmacology
- 키워드
- Allostery
- 키워드
- Chemical biology
- 키워드
- Kinase
- 키워드
- Spectroscopy
- 기타저자
- University of Minnesota Biochemistry Molecular Bio and Biophysics
- 기본자료저록
- Dissertations Abstracts International. 85-11B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520250211151142
■006m o d
■007cr#unu||||||||
■020 ▼a9798382726588
■035 ▼a(MiAaPQ)AAI31234494
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a574.191
■1001 ▼aRasmussen, Damien Matthew.
■24510▼aOn the Allosteric Mechanisms of Paradoxical Activation by RAF Inhibitors
■260 ▼a[Sl]▼bUniversity of Minnesota▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a169 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 85-11, Section: B.
■500 ▼aAdvisor: Levinson, Nicholas M.
■5021 ▼aThesis (Ph.D.)--University of Minnesota, 2024.
■520 ▼aThe type II class of RAF inhibitors currently in clinical trials paradoxically activate BRAF at sub-saturating concentrations. Activation is mediated by induction of BRAF dimers, but why activation rather than inhibition occurs remains unclear. Using biophysical methods tracking BRAF dimerization and conformation, we built an allosteric model of inhibitor-induced dimerization that resolves the allosteric contributions of inhibitor binding to the two active sites of the dimer, revealing key differences between type I and type II RAF inhibitors. For type II inhibitors the allosteric coupling between inhibitor binding and BRAF dimerization is distributed asymmetrically across the two dimer binding sites, with binding to the first site dominating the allostery. This asymmetry results in efficient and selective induction of dimers with one inhibited and one catalytically active subunit. Our allosteric models quantitatively account for paradoxical activation data measured for 11 RAF inhibitors. Unlike type II inhibitors, type I inhibitors lack allosteric asymmetry and do not activate BRAF homodimers. Finally, 19F-NMR data reveal that BRAF homodimers are dynamically asymmetric, with only one of the subunits locked in the active αC-in state. This provides a structural mechanism for how binding of only a single αC-in inhibitor molecule can induce potent BRAF dimerization and activation.
■590 ▼aSchool code: 0130.
■650 4▼aBiophysics
■650 4▼aBiochemistry
■650 4▼aPharmacology
■653 ▼aAllostery
■653 ▼aChemical biology
■653 ▼aForster resonance energy
■653 ▼aKinase
■653 ▼aMagnetic resonance
■653 ▼aSpectroscopy
■690 ▼a0786
■690 ▼a0487
■690 ▼a0419
■71020▼aUniversity of Minnesota▼bBiochemistry, Molecular Bio, and Biophysics.
■7730 ▼tDissertations Abstracts International▼g85-11B.
■790 ▼a0130
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17160964▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
