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Structural Mechanisms of Hedgehog Autoprocessing in Physiology and Disease

Hedgehog自动处理在生理和疾病中的结构机制

基本信息

批准号：
10063481
负责人：
Brian Patrick Callahan
金额：
$ 43.35万
依托单位：
RENSSELAER POLYTECHNIC INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-15 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063481
关键词：
Active Sites Androgen Antagonists Animals Antineoplastic Agents Biological Assay C-terminal Calorimetry Cancer Patient Chemoresistance Cholesterol Cleaved cell Data Development Disease Drug resistance Drug usage Erinaceidae Event Fluorescence Resonance Energy Transfer Gel Hydrolysis In Vitro Kinetics Knowledge Ligands Link Lipids Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Malignant neoplasm of prostate Measures Metals Modification Molecular Biology Mutagenesis N-terminal Pathogenicity Pathway interactions Phase II/III Clinical Trial Physiology Play Process Protein Precursors Protein Splicing Proteins Research Resolution Role Sampling Signal Transduction Specialist Structure Testing Titrations Zinc Zinc deficiency abiraterone base cancer diagnosis castration resistant prostate cancer clinical investigation drug discovery insight intein interdisciplinary approach medical schools novel novel therapeutics premature prevent prostate cancer cell line simulation smoothened signaling pathway structural biology success tumorigenesis

项目摘要

The Hedgehog (Hh) signaling pathway plays important roles in development and in cancer. The Hh ligand, which activates the pathway, is derived from the autoprocessing of the Hh precursor protein. Hh autoprocessing is at the very beginning of the Hh signaling pathway and likely plays crucial roles in both physiology and disease. However, the basic mechanisms of Hh autoprocessing and its role in diseases are poorly understood. Using an interdisciplinary approach, we will define the catalytic mechanism of Hh autoprocessing with atomic resolution and study two novel roles for Hh autoprocessing in prostate cancer. We will first define the catalytic mechanism of Hh autoprocessing with solution NMR; we will then study a new mechanism of tumorigenesis involving zinc deficiency and Hh activation in prostate cancer; lastly we will establish Hh autoprocessing of cancer drugs as a novel means of drug resistance in prostate cancer.

Hedgehog （Hh）信号通路在发育和癌症中发挥重要作用。Hh配体，

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A Single Aspartate Coordinates Two Catalytic Steps in Hedgehog Autoprocessing.

单个天冬氨酸协调刺猬自动加工中的两个催化步骤。

DOI：
10.1021/jacs.6b06928
发表时间：
2016
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Xie,Jian;Owen,Timothy;Xia,Ke;Callahan,Brian;Wang,Chunyu
通讯作者：
Wang,Chunyu

Hedgehog Proteins Consume Steroidal CYP17A1 Antagonists: Potential Therapeutic Significance in Advanced Prostate Cancer.

DOI：
10.1002/cmdc.201600238
发表时间：
2016-09-20
期刊：
ChemMedChem
影响因子：
3.4
作者：
Bordeau BM;Ciulla DA;Callahan BP
通讯作者：
Callahan BP

Subverting Hedgehog Protein Autoprocessing by Chemical Induction of Paracatalysis.

通过化学诱导副催化颠覆刺猬蛋白自动加工。

DOI：
10.1021/acs.biochem.0c00013
发表时间：
2020
期刊：
Biochemistry
影响因子：
2.9
作者：
Smith,CarlJ;Wagner,AndrewG;Stagnitta,RobertT;Xu,Zihan;Pezzullo,JohnL;Giner,José-Luis;Xie,Jian;Covey,DouglasF;Wang,Chunyu;Callahan,BrianP
通讯作者：
Callahan,BrianP

Specificity Distorted: Chemical Induction of Biological Paracatalysis.