CAREER: Dissecting Signal Recognition and Allostery in Ligand-Responsive Biological Functions

这个CAREER项目的目标是了解生物系统如何读取化学信号并将其转化为各种各样的生物输出。对配体反应的改进描述具有从促进对生物控制的一般理解到具有预定义活动的调节系统的设计等意义，这两者在生物医学、工程、环境和生物技术应用中都有广泛的用途。配体响应功能如何识别正确的配体结构，区分不正确的配体结构并将结合事件转化为受控反应？为了更好地了解配体相互作用在调节系统中的功能作用，本项目重点研究BmrR，一种小分子传感基因调节剂，其活性受到许多化学上不同的小分子的刺激。在所描述的工作中，采用生化，生物物理和x射线晶体学方法在结合，功能和结构水平上解剖和检查配体定向效应。目的是将功能，热力学和结构研究结合起来，对配体识别和配体依赖的蛋白质构象控制进行更综合的分析。更广泛的影响更广泛的影响包括通过针对小学、高中和本科学生的机制，更好地将未被充分代表的少数民族与生物和物理科学界联系起来。在小学和高中阶段，这些计划包括继续参与巴尔的摩的项目，在这些项目中，该地区的学生和教师参与以科学为基础的讨论、演示和实践活动。综合研究和教育计划的重点是增加代表性不足的少数民族参与基础科学研究，并为小学、高中和研究生提供培训机会。

Intellectual MeritThe goal of this CAREER project is to understand how biological systems read and transform chemical signals into a diverse range of biological outputs. Improved descriptions of ligand-responses have implications from facilitating a general understanding of biological control to the design of regulatory systems with pre-defined activities, both of which have wide-spread uses in biomedical, engineering, environmental and biotechnological applications. How do ligand-responsive functions recognize the correct ligand structures, discriminate against incorrect ones and transform binding events into controlled responses? To better understand the functional roles of ligand interactions in regulatory systems, this project focuses on BmrR, a small molecule-sensing gene regulator whose activity is stimulated by a number of chemically diverse small-molecules. In the described work, biochemical, biophysical and X-ray crystallographic approaches are employed to dissect and examine ligand-directed effects at the binding, functional and structural levels. The aim is to combine functional, thermodynamic and structural studies into a more integrative analysis of ligand recognition and ligand-dependent control of protein conformation. Broader ImpactThe broader impacts involve better connecting underrepresented minorities with the biological and physical science communities through mechanisms that target students at the elementary, high school and undergraduate levels. At the elementary and high school levels, these plans include continued involvement in Baltimore-based programs in which students and teachers in the area participate in science-based discussions, demonstrations and hands-on activities. The integrated research and educational plans focus on increasing the participation of underrepresented minorities in basic science research and providing training opportunities for elementary, high school and graduate students.