Structural Biology of Cellular Signaling

My laboratory investigates cellular signaling at the molecular level. We use X-ray crystallograpy in conjunction with biochemical and other biophysical methods to study Nitric Oxide Synthases, Soluble Guanylyl Cyclases, Toll / IL-1 receptors, Hypoxia-inducible factor(s), and signaling molecules that regulate Axon Guidance.

Cells encounter a constant barrage of signals that convey information to ensure autonomic cell regulation of physiological activity and homeostasis. Signal transduction is the process by which these signals are transformed into physicochemical perturbations of networks of key molecules inside the cell. Complexity of these biochemical networks stems from the large number of components in the system and their ability to interact with exquisite temporal and spatial precision. The activation of these signaling cascades is incumbent upon the nature of the signal(s); like a computational network it leads to the transmission of signals to specific targets culminating in an appropriate cellular response. Despite the enormous complexity of these networks, structural and functional study of signal transduction molecules and their interactions with other proteins provides valuable insights into systems biology, namely cellular signaling pathways at work in normal and pathological conditions.

Currently, a "hot" area of research in cell signaling deals with understanding the molecular basis of signal transduction by gaseous messengers such as nitric oxide (NO), carbon monoxide (CO), and molecular oxygen (O₂). NO is synthesized in the body by a family of enzymes called Nitric Oxide Synthases (NOS) and CO is generated as a by-product of heme degradation by the enzyme Heme Oxygenase. A long-standing collaboration with Prof. Bettie Sue Masters' laboratory has led to unexpected structural insights into catalytic and functional aspects of NO signaling. Future studies will focus on electron transfer mechanisms, isoform-specific inhibitor design, function of the cofactor tetrahydrobiopterin, protein-protein interactions, and structural/mutagenesis study of NO synthases.

My laboratory has recently identified and characterized novel NOS-like proteins in prokaryotes. Sructure-function studies on this ancestral signal transduction system is underway towards identifying new pathways in which NO functions as a signal transducer.

We are also investigating the structure of soluble guanylyl cyclase (sGC) which functions as a hemoprotein receptor for NO. Upon activation by NO, sGC converts GTP to the second messenger cGMP which plays a key role in physiological events such as vascular smooth muscle relaxation, platelet aggregation, and neuronal signaling.