Professor Benoit Roux
Department of Pediatrics
The University of Chicago
Chicago, IL

Monday, April 23, 2007
3:00 pm (CT)
3269 Beckman Institute

Abstract

Numerous biological processes involve large scale conformational changes triggered by various chemical signals. A powerful tool to characterize such processes is to compute the thermodynamics free energy surface governing the conformational changes. In this seminar, I will describe recent work on Src tyrosine kinases, the glutamate receptors, and on the potassium channel. Regulation of the enzymatic activity of Src relies on the reversible assembly of a three-domain complex, made up of a catalytic domain and a tandem of small binding modules, SH2 and SH3, connected by a small polypetide stretch. Mutations in this flexible connector have a dramatic effect on the regulation of the kinase, but whether they affect the inactivated assembled form of the enzyme or the activated disassembled form is not completely clear. The ionotropic glutamate receptors (GluRs) are ligand-gated ion channels that couple agonist binding at a soluble ligand-binding core to the opening of a transmembrane ion channel, allowing the entry of cations into the neuron, causing depolarization. The ligand binding is the basic mechanism to transduce the chemical signal into channel openings. But how the free energy of agonist binding is converted into mechanical work to drive transmembrane pore opening remains unknown. In the open state, the KcsA potassium channel conducts K+ ions at a rate near diffusion-limit. But why the channel rapidly inactivates and stops conducting is not known.