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Structure and Function of the Vibrio cholerae Master Virulence Regulators HapR and ToxT
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| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | Structure and Function of the Vibrio cholerae Master Virulence Regulators HapR and ToxT. |
| 개인저자 | Cruite, Justin Thomas. |
| 단체저자명 | Dartmouth College. Biochemistry. |
| 발행사항 | [S.l.]: Dartmouth College., 2019. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2019. |
| 형태사항 | 123 p. |
| 기본자료 저록 | Dissertations Abstracts International 81-03B. Dissertation Abstract International |
| ISBN | 9781085631365 |
| 학위논문주기 | Thesis (Ph.D.)--Dartmouth College, 2019. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 81-03, Section: B.
Advisor: Kull, F. Jon. |
| 이용제한사항 | This item must not be sold to any third party vendors. |
| 요약 | Vibrio cholerae is the gram-negative bacteria that causes the diarrheal disease cholera. Ingestion of water contaminated with V. cholerae can lead to severe dehydration and death. Gene expression in V. cholerae is regulated by environmental stimuli to ensure the optimal spacio-temporal expression of virulence factors. The aim of this work was to determine the mechanisms by which physiological ligands and synthetic inhibitors allosterically regulate the activity of two master regulators from V. cholerae, HapR and ToxT.HapR is a member of the TetR-family of transcriptional regulators and is the master quorum-sensing regulator of V. cholerae. The natural ligand of HapR is unknown. To gain insight into the mechanism of allosteric regulation of HapR activity by the unknown ligand, the crystal structure of an inactive natural variant of HapR containing a glycine to aspartate substitution in the hinge region of the DNA-binding domain was determined. The structure suggests that the variant could be unable to bind DNA because the aspartate located in the hinge would clash with the phosphate backbone. Further analysis of the structure revealed that the variant is less flexible than functional HapR, suggesting that ligand binding to HapR could allosterically regulate the protein by influencing its flexibility.ToxT is an AraC/XylS-family member that directly activates the expression of virulence genes in V. cholerae. The unsaturated fatty acids (UFAs) found in bile and synthetic inhibitors designed to mimic them inhibit ToxT dimerization and DNA binding. Only UFA and inhibitor-bound structures of ToxT were previously determined. To gain insight into the mechanism of allosteric regulation of ToxT function by UFAs and synthetic inhibitors, the crystal structure of apo ToxT has been determined. The structure has revealed that the release of the UFA or inhibitor increases the flexibility of ToxT, which allows it to assume an active conformation, suggesting that UFAs and synthetic inhibitors inhibit ToxT by reducing flexibility and restraining ToxT in a conformation that is unable to dimerize or bind DNA. Small angle X-ray scattering was then used to validate a model of a an active ToxT dimer bound to DNA. |
| 일반주제명 | Biochemistry. Molecular biology. Microbiology. |
| 언어 | 영어 |
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