Tina Iverson
X-ray crystallography of integral membrane protein complexes
The determination of structures of any protein is essential for the understanding
protein function. Integral membrane proteins represent at least 30% of open
reading frames in the genome and approximately 50% - 70% of pharmacological
therapeutic targets. Despite their medical importance, they comprise only ~50
unique structures in the protein data base, as opposed to the >25,000 structures
available for soluble proteins. The Iverson laboratory specializes in understanding
the structure-function relationships in membrane proteins using x-ray crystallography
as the primary tool. We are investigating several broad categories of membrane
proteins including respiratory proteins, ion channels, and receptors.
Respiratory systems require integral membrane proteins to establish a transmembrane
proton gradient used for ATP synthesis. Different organisms utilize different
respiratory systems to help establish this electrochemical gradient, but the
mechanisms are similar and the proteins mediating the process sometime use common
architectures. During mitochondrial respiration, respiratory complex II converts
succinate to fumarate in the Krebs cycle and passes the electrons to quinone
molecules bound in the transmembrane region. I have previously determined the
initial structure of a complex II homolog from E. coli and we are now using this
information to direct further biochemical and structural studies. Some organisms
with alternative respiratory systems can utilize nitric oxide (NO), a component
of smog, as a respiratory metabolite. Pathogenic bacteria perform NO conversion
to neutralize the NO secreted by host defense mechanisms and evade immunological
responses. We are studying several enzymes that catalyze NO conversions to understand
the chemistry of these reactions in biological systems.
Ion channels mediate all excitable processes in cells, and their hallmark characteristics
include exquisite selectivity and rapid translocation of ions across the membrane.
The open probability of ion channels physiologically can be modulated by a variety
of different stimuli. The allure of structural studies on ion channels arises
from the unrivaled information gained through the direct observation of interactions
between the protein and the permeant ion. We are using structural techniques
to understand the gating of ion channels and gain further insights into their
selectivity.
Receptors are perhaps the most interesting membrane proteins to study using structural
techniques. These proteins represent a very large number of drug targets, and
elucidating the structures of receptors in their inactive and activated forms
as well as in complex with the soluble proteins that initiate signal cascades
can aid in structure-based drug design.
In addition to looking at structures in specific systems, research in the Iverson
laboratory will work to develop techniques to make membrane protein crystallography
more tractable.
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