Allosteric control of loop motions

循环运动的变构控制

• 批准号: 1615415
• 负责人: joseph loria
• 金额: $ 90万
• 依托单位: Yale University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1615415&HistoricalAwards=false
• 关键词: Allosteric; control; loop; motions

Enzymes are critical for life. Understanding how the atoms in enzymes move during the chemical reactions they catalyze is integral for the design of enzymes that would catalyze novel reactions and would lead to advances in the fields of biotechnology and drug design. This research aims to impact these fields through the characterization of enzyme motions and their importance to catalytic function. In addition to the direct impact on differing scientific areas, this project will result in the training of postdoctoral scientists in state-of-the-art biophysical techniques to enable their transition to independent researchers. Moreover, this project will recruit and train undergraduates, from underrepresented groups, in modern biophysical research.The mechanism by which the catalytic activity of enzymes is regulated often involves the relay of structural or dynamical perturbations in the enzyme between a distant (allosteric) site and the catalytic (active) site. This project will examine the allosteric regulation of the human enzyme, protein tyrosine phosphatase 1B (PTP1B) using solution nuclear magnetic resonance (NMR) and computational methods coupled with biochemical experiments. These methods will enable examination of the kinetics, thermodynamics, and mechanism of motions in PTP1B. The goals of this project will be to understand how allosteric changes can be relayed over long molecular-scale distances and influence chemical reactivity. These goals will be achieved by characterizing how the binding of small, organic molecules at an allosteric site changes the structure and atomic flexibility of amino acids at the active site. In addition, studies will be performed to examine the natural allosteric site in PTP1B that is utilized in vivo to regulate its catalytic activity. This combination of experiments will provide new insight into PTP1B function and into general allosteric models applicable to numerous other important enzymes.

酶对生命至关重要。了解酶中的原子在它们催化的化学反应过程中如何移动，对于催化新反应的酶的设计是不可或缺的，并将导致生物技术和药物设计领域的进步。本研究旨在通过酶运动的表征及其对催化功能的重要性来影响这些领域。除了对不同科学领域的直接影响外，该项目还将导致对博士后科学家进行最先进的生物物理技术培训，使他们能够过渡到独立的研究人员。此外，该项目将从代表性不足的群体中招募和培训现代生物物理研究的本科生。酶催化活性的调节机制通常涉及酶中远距离（变构）位点和催化（活性）位点之间的结构或动力学扰动的传递。该项目将研究人类酶，蛋白酪氨酸磷酸酶1B（PTP1B）的变构调节，使用溶液核磁共振（NMR）和计算方法结合生化实验。这些方法将使检查的动力学，热力学和运动机制的PTP1B。该项目的目标是了解变构变化如何在长分子尺度的距离上传递并影响化学反应性。这些目标将通过表征小的有机分子在变构位点的结合如何改变活性位点氨基酸的结构和原子灵活性来实现。此外，还将进行研究，以检查PTP1B中用于体内调节其催化活性的天然变构位点。这种实验的结合将提供新的洞察PTP1B功能和一般变构模型适用于许多其他重要的酶。