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Visualizing a Dynamic Allosteric Network in Human Herpesvirus Proteases With an Inhibitory Antibody.
Visualizing a Dynamic Allosteric Network in Human Herpesvirus Proteases With an Inhibitory Antibody.
상세정보
- 자료유형
- 학위논문
- Control Number
- 0017164721
- International Standard Book Number
- 9798346877233
- Dewey Decimal Classification Number
- 574
- Main Entry-Personal Name
- Zimanyi, Marcell Antal.
- Publication, Distribution, etc. (Imprint
- [S.l.] : University of California, San Francisco., 2024
- Publication, Distribution, etc. (Imprint
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- Physical Description
- 71 p.
- General Note
- Source: Dissertations Abstracts International, Volume: 86-06, Section: B.
- General Note
- Advisor: Cheng, Yifan.
- Dissertation Note
- Thesis (Ph.D.)--University of California, San Francisco, 2024.
- Summary, Etc.
- 요약Exploiting conformational dynamics is a powerful method for inhibiting enzymes and can produce new allosteric inhibitors for managing disease. In this work, we outline the discovery and characterization of an antibody fragment called Fab5 which inhibits the human Cytomegalovirus protease (HCMV Pr). Using ensemble biophysical techniques, we describe the dynamic relationship between Fab5 and HCMV Pr, from which we propose a mechanism of inhibition along with potential insights into the broader conformational network that controls all human Herpesvirus Protease (HHV Pr) activation. Mutagenesis and biochemical characterization allow us to validate our hypotheses in vitro. We provide novel tools and strategies for HHV Pr inhibition that we believe can be leveraged in future therapeutic development. In Chapter 1.1, we use cryogenic electron microscopy (cryo-EM) to reveal the Fab5 binding site on HCMV Pr which we call the Latch Loop. We propose that Fab5 inhibits HCMV Pr by preventing dimerization through an allosteric mechanism that is both mechanistic and dynamic, ultimately preventing the protease from activating. Mutagenic studies demonstrate the previously unrecognized importance of the Latch Loop in the conformational network that links dimerization to HHV Pr activation. In Chapter 1.2, we use X-ray radiolytic Footprinting to survey solvent accessibility changes on HCMV Pr after Fab5 binding. These studies reveal a residue network near the HCMV Pr active site that influences dimerization and, thus, activity despite being buried in the center of the protease.
- Subject Added Entry-Topical Term
- Biochemistry.
- Subject Added Entry-Topical Term
- Biophysics.
- Subject Added Entry-Topical Term
- Microbiology.
- Subject Added Entry-Topical Term
- Chemistry.
- Index Term-Uncontrolled
- Antibody
- Index Term-Uncontrolled
- Cryogenic electron microscopy
- Index Term-Uncontrolled
- Cytomegalovirus
- Index Term-Uncontrolled
- Herpes
- Index Term-Uncontrolled
- Phage-display
- Index Term-Uncontrolled
- Protease
- Added Entry-Corporate Name
- University of California, San Francisco Chemistry and Chemical Biology
- Host Item Entry
- Dissertations Abstracts International. 86-06B.
- Electronic Location and Access
- 로그인을 한후 보실 수 있는 자료입니다.
- Control Number
- joongbu:656413
MARC
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■006m o d
■007cr#unu||||||||
■020 ▼a9798346877233
■035 ▼a(MiAaPQ)AAI31637762
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a574
■1001 ▼aZimanyi, Marcell Antal.▼0(orcid)0000-0003-1981-1244
■24510▼aVisualizing a Dynamic Allosteric Network in Human Herpesvirus Proteases With an Inhibitory Antibody.
■260 ▼a[S.l.]▼bUniversity of California, San Francisco. ▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a71 p.
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-06, Section: B.
■500 ▼aAdvisor: Cheng, Yifan.
■5021 ▼aThesis (Ph.D.)--University of California, San Francisco, 2024.
■520 ▼aExploiting conformational dynamics is a powerful method for inhibiting enzymes and can produce new allosteric inhibitors for managing disease. In this work, we outline the discovery and characterization of an antibody fragment called Fab5 which inhibits the human Cytomegalovirus protease (HCMV Pr). Using ensemble biophysical techniques, we describe the dynamic relationship between Fab5 and HCMV Pr, from which we propose a mechanism of inhibition along with potential insights into the broader conformational network that controls all human Herpesvirus Protease (HHV Pr) activation. Mutagenesis and biochemical characterization allow us to validate our hypotheses in vitro. We provide novel tools and strategies for HHV Pr inhibition that we believe can be leveraged in future therapeutic development. In Chapter 1.1, we use cryogenic electron microscopy (cryo-EM) to reveal the Fab5 binding site on HCMV Pr which we call the Latch Loop. We propose that Fab5 inhibits HCMV Pr by preventing dimerization through an allosteric mechanism that is both mechanistic and dynamic, ultimately preventing the protease from activating. Mutagenic studies demonstrate the previously unrecognized importance of the Latch Loop in the conformational network that links dimerization to HHV Pr activation. In Chapter 1.2, we use X-ray radiolytic Footprinting to survey solvent accessibility changes on HCMV Pr after Fab5 binding. These studies reveal a residue network near the HCMV Pr active site that influences dimerization and, thus, activity despite being buried in the center of the protease.
■590 ▼aSchool code: 0034.
■650 4▼aBiochemistry.
■650 4▼aBiophysics.
■650 4▼aMicrobiology.
■650 4▼aChemistry.
■653 ▼aAntibody
■653 ▼aCryogenic electron microscopy
■653 ▼aCytomegalovirus
■653 ▼aHerpes
■653 ▼aPhage-display
■653 ▼aProtease
■690 ▼a0487
■690 ▼a0786
■690 ▼a0410
■690 ▼a0485
■71020▼aUniversity of California, San Francisco▼bChemistry and Chemical Biology.
■7730 ▼tDissertations Abstracts International▼g86-06B.
■790 ▼a0034
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17164721▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
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