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  

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Control Number  

joongbu:656413