Research Description

The goal of research in my lab is to characterize the structure and mechanism of activation of G protein coupled receptors (GPCRs). My lab has employed a variety of approaches including cell biology, gene disruption in mice, and in vivo physiology to determine the role of specific adrenergic receptor subtypes in normal physiology.  During the past 15 years we have applied a spectrum of biochemical and biophysical tools to study different aspects of GPCR structure and activation.  In 2007 we obtained two crystal structures of the beta2 adrenergic receptor (beta2AR): as a b2AR-Fab complex and as a beta2AR-T4L fusion protein. These were the first structures of a hormone/neurotransmitter activated GPCR. The method that we developed to obtain crystals of the beta2AR (generating T4 lysozyme fusion proteins) has subsequently been used to crystallize twelve other GPCRs including the following structures from our lab: the M2 and M3 muscarinic receptors, the mu- and delta-opioid receptors, and the protease activated receptor (PAR1). These structures all represent inactive states of these GPCRs.  More recently we have succeeded in obtaining active state structures of the b2AR including the b2AR-Gs complex. These crystallography studies provide high-resolution snap-shots of transmembrane signaling by G protein coupled receptors, as well as insights into the structural basis for ligand binding specificity.

My lab also has a great interest in the contribution of protein dynamics to the functional versatility of GPCRs. Our approaches to obtain GPCR crystal structures have been guided by insights from biochemical and biophysical studies aimed at characterizing their dynamic behavior. We are currently exploring the use of NMR and EPR spectroscopy to provide additional insights into the dynamic properties of GPCRs.