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Design and Evolution of Metal-Based Functions in Supramolecular Protein Scaffolds

超分子蛋白支架中金属基功能的设计与演化

基本信息

批准号：
10413065
负责人：
Faik Akif Tezcan
金额：
$ 31.24万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10413065
关键词：
Address Affinity Amides Architecture Automobile Driving Binding Biochemistry Bioinorganic Chemistry Biology Biomimetics Catalysis Cell Respiration Cell physiology Chemistry Complex Cytochromes Dioxygen Directed Molecular Evolution Elements Engineering Environment Esters Evolution Genetic Transcription Geometry Goals Health Human Hydrogen Bonding Hydrolase Hydrolysis Ions Knowledge Lead Mediating Metal Ion Binding Metalloproteins Metals Methods Mutation Natural Products Organism Oxidation-Reduction Pathway interactions Peptides Phosphoric Monoester Hydrolases Property Protein Engineering Proteins Reaction Research Research Project Grants Respiration Scaffolding Protein Series Spectrum Analysis Structure Structure-Activity Relationship Surface Testing Thermodynamics Time Transition Elements amidase base beta-Lactamase design design and construction dimer esterase flexibility improved knowledge of results metal complex metalloenzyme microbial neurotransmission novel novel strategies oxidation polypeptide programs protein structure rational design rational function scaffold self assembly

项目摘要

Metalloproteins carry out many cellular functions that are central to biology and human health. While our knowledge of how metalloproteins function has grown immensely thanks to technological advances, we still possess only a superficial understanding of the interplay between protein structure/dynamics and metal coordination/reactivity. As a result, it has not yet been possible a) to predict the functional mechanism of metalloproteins simply by looking at their structures, b) to emulate or improve upon the structures and functions of metalloproteins by de novo design, and c) to understand how complex bioinorganic functions may have emerged on simple peptide/protein scaffolds during natural evolution. The overarching goal of the proposed research program is to address these three challenges by designing and constructing protein scaffolds with increasingly more complex metal-based functions from scratch. Inspired by a hypothetical pathway for the natural evolution of metalloproteins, we have recently developed new approaches to metalloprotein design in which monomeric proteins are templated by metal ions to form novel supramolecular assemblies. The interfaces of these evolutionarily naïve complexes are then engineered and evolved to create self-standing protein architectures with complex metal-based functions. In the proposed research, we will further develop these “metal-templated protein design” strategies by capitalizing on two new protein scaffolds developed in our lab (DiCyt and TriCyt), which provide easy access to diverse metal coordination geometries, secondary-sphere environments and global properties (tunable structures, oligomeric states, flexibility/rigidity) that are difficult to attain with other protein design strategies. We will use DiCyt and TriCyt scaffolds to build metalloprotein assemblies for stable and selective coordination of first-row transition metal ions (Specific Aim 1), for challenging ester, amide and phospho-ester bond hydrolysis reactions (Specific Aim 2), and for redox catalytic reactions involving dioxygen binding and activation (Specific Aim 3). These efforts will not only uncover fundamental structure-function relationships that govern diverse metalloprotein activities, but also lead to better understanding of how bioinorganic complexity emerges in simple protein scaffolds.

金属蛋白执行许多对生物学和人类健康至关重要的细胞功能。当我们