Structural mechanisms for ABC multidrug transporter selectivity and transport

ABC 多药物转运蛋白选择性和转运的结构机制

基本信息

批准号：
9139965
负责人：
Thomas Michael Tomasiak
金额：
$ 9万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9139965
关键词：
ABCG2 gene ATP-Binding Cassette Transporters Active Sites Advisory Committees Amino Acids Architecture Automobile Driving Bacterial Drug Resistance Binding Binding Sites Biological Biological Assay Biological Models Blood - brain barrier anatomy Characteristics Chemicals Clostridium perfringens Collaborations Complex Coupling Cryoelectron Microscopy Crystallography Development Discipline Disease Drug Design Drug Kinetics Drug Transport Drug resistance Event Fab Immunoglobulins Family Future Goals Health Homeostasis Homologous Gene Human Human body Hybrids Institution Kidney Diseases Knowledge Lateral Lead Life Ligand Binding Ligands Lipids Liver diseases Malignant Neoplasms Maps Mass Spectrum Analysis Mechanics Membrane Membrane Proteins Mentors Modeling Molecular Molecular Conformation Multi-Drug Resistance Mutagenesis Mutation Neurodegenerative Disorders Nucleotides Nutrient Pathogenesis Peptide Transport Peptides Permeability Pharmaceutical Preparations Pharmacogenomics Play Positioning Attribute Process Property Proteins Research Research Personnel Resolution Roentgen Rays Role Saccharomyces cerevisiae Senior Scientist Specificity Structural Models Structure Structure-Activity Relationship Substrate Cycling Substrate Specificity System Techniques Testing Thermus thermophilus Training Training Programs Transmembrane Transport Validation Work X-Ray Crystallography base career clinically relevant design drug distribution family structure innovation interest microbial monomer multi drug transporter mutant novel peptide drug personalized medicine professor protein complex public health relevance screening surfactant thermostability tool

项目摘要

DESCRIPTION (provided by applicant): ABC transporters govern distribution of drugs, lipids, and peptides throughout the human body and play a critical role in multidrug resistance. This proposal aims to understand the entire transport cycle of an ABC transporter and identify rules governing how different ABC transporters select substrates by using a powerful combination approach combining x-ray crystallography and cryo electron microscopy. The approach outlined here examines the mechanistic cycle of an ABC transporter, from substrate binding to conformational changes using a cryo electron microscopy (cryo-EM) approach that has yielded an unprecedented subnanometer resolution structure of an ABC transporter in a collaboration Dr. Tomasiak was part of with Dr. Yifan Cheng. The ultimate goal is a comprehensive model of several human transporters to reveal a quantitative model of human pharmacokinetics and pharmacogenomics that will give a clearer understanding of how these biologically critical molecules are distributed. The candidate, Thomas Tomasiak, has an interest to use the K99 to launch an independent career weaving several biological disciplines and approaches to studying distribution of drugs, lipids, and other hydrophobic compounds. Dr. Tomasiak hopes to become an innovate assistant professor at a leading institution, contributing to our knowledge of drug disposition and multidrug resistance in microbial pathogenesis and cancer. This proposal is centered on a training program in cryo-EM that will help Dr. Tomasiak become an expert in this field and combine it with his background in x-ray crystallography. The combination of membrane protein crystallography and cryo-EM will make a powerful hybrid approach to answer biological questions concerning conformational state changes and complexes in membrane proteins difficult for either technique alone. Part of the proposed research is in development of new tools for the validation of structural models from cryo-EM. The proposal is designed to supplement Thomas's training by integrating his current knowledge of membrane proteins and x-ray crystallography with the burgeoning field of cryo-electron microscopy. Dr. Tomasiak's mentor, Dr. Stroud, and co-mentor, Dr. Cheng are internationally recognized in their fields and Dr. Stroud has supported numerous postdoctoral researchers into the transition to independence. In addition to the co-mentors, Dr. Tomasiak has assembled an advisory committee of senior scientists who will be able to help guide his research and are ideally situated to guide his career progression to an independent position.

描述（应用程序提供）：ABC转运蛋白控制着在整个人体中的药物，脂质和胡椒粉的分布，并在多药耐药性中起关键作用。该提案旨在了解ABC转运蛋白的整个运输周期，并确定不同的ABC转运蛋白如何使用强大的组合方法结合X射线晶体学和冷冻电子显微镜的规则。此处概述的方法研究了ABC转运蛋白的机理周期，从使用冷冻电子显微镜（Cryo-EM）方法结合到宪法变化，该方法产生了ABC Transporter在协作中的ABC Transporter的前所未有的亚纳光分辨率结构，Tomasiak博士与Yifan Cheng博士是一部分。最终目标是几个人类转运蛋白的综合模型，以揭示人类药代动力学和药理学的定量模型，该模型将对这些生物学上关键的分子的分布方式有更清晰的了解。候选人托马斯·托马西亚克（Thomas Tomasiak）有兴趣使用K99发起独立的职业，编织了几个生物学学科和方法，以研究药物，脂质和其他疏水性化合物的分布。 Tomasiak博士希望成为一家领先机构的创新助理教授，这有助于我们对微生物发病机理和癌症中药物处置和多药耐药的了解。该建议集中在Cryo-EM的一项培训计划上，该计划将帮助Tomasiak博士成为该领域的专家，并将其与X射线晶体学的背景相结合。膜蛋白质晶体学和冷冻EM的结合将制作出强大的混合方法，以回答有关构象状态变化和复合物的生物学问题，而这种膜蛋白中的复合物对于任何一种技术来说都是难以单独使用的。拟议的研究的一部分是开发用于验证Cryo-EM结构模型的新工具。该提案旨在通过将其当前对膜蛋白和X射线晶体学的知识与低温电子显微镜的迅速发展进行整合，以补充托马斯的训练。托马西亚克（Tomasiak）博士的精神，斯特劳德（Stroud）博士和郑博士（Cheng）博士在其领域得到了国际认可，斯特劳德（Stroud）博士支持众多博士后研究人员，以实现向独立的过渡。除了院长外，Tomasiak博士还组建了一个高级科学家的咨询委员会，他们将能够帮助指导他的研究，理想地指导他的职业生涯发展到独立位置。