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Structural Characterizations of Transient and Heterogeneous Protein Complexes

瞬时和异质蛋白质复合物的结构表征

基本信息

批准号：
8225883
负责人：
Nozomi Ando
金额：
$ 9万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-02 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8225883
关键词：
Allosteric Regulation Amino Acids Antineoplastic Agents Arakawa syndrome 2 Behavior Biochemical Biological Process Biology Cell Cycle Cells Chemicals Complement Complex Congenital Abnormality Crystallization Crystallography DNA biosynthesis Data Deoxyribonucleotides Disease Drug Delivery Systems Drug Design Effectiveness Enzymes Escherichia coli Funding Gene Mutation Goals Heart Human Individual Investigation Kinetics Learning Link Malignant Neoplasms Megaloblastic Anemia Mentors Metabolism Methionine Methods Modeling Molecular Biology Molecular Conformation Nature Neural tube Nucleotides Organism Pharmaceutical Preparations Phase Physiological Play Pregnancy Protein Isoforms Proteins Regulation Research Ribonucleotide Reductase Roentgen Rays Role S-Adenosylmethionine Sampling Solutions Spectrum Analysis Structure System Time Training Vitamin B 12 Work analytical ultracentrifugation base flexibility in vivo insight meetings prevent protein complex

项目摘要

DESCRIPTION (provided by applicant): Transient and heterogeneous protein interactions play important roles both in the catalytic and regulatory functions of protein complexes and multi-modular machinery. However, the technical challenges involved in structural characterizations of such systems have placed critical barriers against understanding their intrinsic behavior. The vitamin B12-dependent methionine synthase and class Ia ribonucleotide reductases are two enzymes that epitomize such systems where structural insight into their multiple conformations will advance our understanding of their physiological and medically relevant behavior. To meet the technical challenge of investigating these systems, I will exploit the ensemble structural information that can be gained by small- and wide-angle X-ray scattering and employ mathematical methods to deconvolute the mixtures into quantifiable individual states. This work will be complemented by crystallography, spectroscopy, and analytical ultracentrifugation. PUBLIC HEALTH RELEVANCE: Ribonucleotide reductase is a protein found in all organisms that is an important target for cancer drugs, and methionine synthase is an important protein in healthy pregnancies. By investigating the structure of these "floppy" proteins that have been challenging to study, we will gain better insight into drug design targeting ribonucleotide reductase and genetic mutations in methionine synthase.

描述（由申请人提供）：瞬时和异质蛋白质相互作用在蛋白质复合物和多模块机制的催化和调节功能中发挥重要作用。然而，这些系统的结构表征所涉及的技术挑战对理解其内在行为设置了关键障碍。维生素B12依赖性甲硫氨酸合酶和Ia类核糖核苷酸还原酶是两种酶，概括了这样的系统，其中对它们的多种构象的结构洞察将促进我们对其生理和医学相关行为的理解。为了应对调查这些系统的技术挑战，我将利用可以通过小角度和广角X射线散射获得的整体结构信息，并采用数学方法将混合物解卷积为可量化的单个状态。这项工作将由晶体学，光谱学和分析超离心补充。公共卫生相关性：核糖核苷酸还原酶是在所有生物体中发现的蛋白质，是癌症药物的重要靶点，而甲硫氨酸合酶是健康妊娠中的重要蛋白质。通过研究这些一直具有挑战性的“松软”蛋白质的结构，我们将更好地了解靶向核糖核苷酸还原酶和甲硫氨酸合酶基因突变的药物设计。