Associate Professor
Protein structure and function
Heme proteins
X-ray crystallography
Research in the Hargrove laboratory involves the structure,
function, folding, and expression of heme proteins. Heme proteins exhibit
marked differences in reactivity toward diatomic ligands such as O2,
CO, and NO, all of which are important biological molecules. However,
unlike most enzymatic reactions which rely on the exact shape and charge
distribution of the substrate molecule to determine specificity, selective
recognition of small diatomic ligands by heme proteins occurs after
the heme-ligand complex is formed.
Myoglobin and hemoglobin have long been ideal systems for developing
an understanding of the relationship between the structure and function
of proteins. More recently, these proteins have found renewed interest
due to the application of modern methods of time-resolved crystallography,
site-directed mutagenesis, and molecular dynamics to explore molecular
recognition and ligand binding with high resolution. Furthermore, heme
proteins which are less understood physiologically and biophysically
have been discovered which appear to have a wide variety of novel signaling
and oxygen storage functions. My laboratory uses site-directed mutagenesis,
kinetic and spectroscopic methods, and X-ray crystallography to study
the high resolution structure and function of heme proteins. There are
three projects currently underway:
1. Structure and function of plant hemoglobins. Plants contain two kinds
of hemoglobins. Those that fix nitrogen in symbiosis with bacteria have
oxygen transport (leg)hemoglobins, and all plants have nonsymbiotic
hemoglobins whose function likely relate to molecular signaling and
scavenging. We are interested in the latter group of proteins because
their structures are unusual, having bis-histidyl coordinating of the
heme iron. Our goal is to understand how these "hexacoordinate"
hemoglobins are able to bind ligands like oxygen, nitric oxide, and
carbon monoxide in spite of intramolecular competition from a histidine
side chain. Eventually we would like to relate their chemical behavior
to physiological function. Our interest in leghemoglobins is centered
on a goal of understanding the evolution of oxygen transport in plants.
The leghemoglobins evolved from nonsymbiotic hemoglobins ~ 200 million
years ago, and we are using biophysical methods to investigate the structural
events that led to this important event in evolution.
2. Structure and function of human hexacoordinate hemoglobins. Humans
contain two hexacoordinate hemoglobins; neuroglobin and cytoglobin.
We are interesting in their structure, ligand binding behavior, and
potential structural and functional relationships to hexacoordinate
plant hemoglobins. Neuroglobin is found in neural tissue and the retina.
Cytoglobin is found in many tissues. Likely functions of these proteins
include signaling and NO scavenging. Our goals are to use structure
and biophysics to decipher potential functions and understand the chemical
role of hexacoordination in these systems.
3. Bacterial hexacoordinate hemoglobins. Some cyanobacteria also contain
hexacoordinate hemoglobins. These proteins are unusual in having a covalent
bond between a His side chain and a heme vinyl. We are investigating
the role of this covalent bond along with the structure and function
of these proteins. Furthermore, this organism is readily amenable to
genetic manipulation so we are working toward understanding physiological
function using reverse genetic methods.
