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

Johns Hopkins University, Baltimore MD

Investigators

Abstract

Intellectual Merit The 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 Impact The 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.