The overall goal of my research is to elucidate the molecular intricacies of enzyme mechanism and
receptor activation and using that knowledge to develop inhibitors and activators for pharmaceutical purposes.
Our projects range from cell signaling proteins such as guanylyl cyclases (blood pressure, vision, and bone growth)
to beta-lactamases (responsible for the current epidemic antibiotic resistance).
Our lab employs state of the art multi-disciplinary biophysical, biochemical, crystallographic, molecular biology, and cell biology techniques.
The guanylyl cyclases can be either membrane bound or soluble and are activated by either peptides or nitric oxide (NO),
respectively. Our lab has recently published on new insights regarding the dimerization, NO and BAY58-2667 activation
of the soluble guanylyl cyclase. Our structural studies are also aimed at developing new activators to treat
cardiovascular diseases such as heart-failure, hypertension, erectile dysfunction, and atherosclerosis and involves a
pre-clinical collaboration with pharmaceutical industry.
The beta-lactamase project entails the structure-function studies of these enzymes and investigating their modes of
becoming resistant to antibiotics and inhibitors. We employ a novel synergistic Raman/X-ray crystallographic approach
to allowed detailed time-dependence and structural information of intermediate formation of inhibitors and antibiotics.
We have used this information to improve inhibition aspects of clinical and novel inhibitors via the rational drug design
cycle. Our structure-based drug design efforts to combat antibiotic resistance involves clinician researchers, a medicinal
chemist team, and structural biologists as well as pharmaceutical industry connections (this project is in collaboration
with Drs. Bonomo, Helfand, Carey, and Buynak).
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