ficity and is in part responsible for the remarkable 
selectivities exhibited by most enzymes for their 
substrates, by transport systems for their nutrient, by 
antibodies for their antigens, and by virus or bacteria 
for their host. Largely through use of x-ray crystallog- 
raphy. Investigator Florante A. Quiocho, Ph.D. (Bay- 
lor College of Medicine) and his colleagues are 
studying the structures of a number of proteins in 
order to understand at the atomic level the features 
associated with a variety of protein-ligand interac- 
tions. These include adenosine deaminase, an en- 
zyme required in the normal development of the 
immune response; calmodulin, a key protein in the 
activation of target proteins; two antibodies, one 
raised against a coat protein of the AIDS virus and the 
other against surface polysaccharide of a bacterium; 
aldose reductase, an enzyme believed responsible 
for some diabetic complications; and several peri- 
plasmic receptor proteins with specificity for carbo- 
hydrates, oxyanions, and amino acids involved in 
active transport and chemotaxis in bacterial cells. 
The laboratory of Associate Investigator Stephen 
R. Sprang, Ph.D. (University of Texas Southwestern 
Medical Center at Dallas) has focused on x-ray struc- 
tural studies of proteins that regulate cellular pro- 
cesses. These include hormones such as tumor ne- 
crosis factor and fibroblast growth factor (FGF), 
both of which are implicated in the induction of cell 
growth, differentiation, and in the case of FGF, on- 
cogenesis. The group is also interested in the mecha- 
nisms by which the signals induced by the interac- 
tion of such hormones with cellular receptors are 
coupled to specific intracellular events. Ongoing 
structural studies of the a subunit of Gi protein, 
which couples the muscarinic receptors to activa- 
tion of potassium channels, are intended to illumi- 
nate the molecular basis of signal transduction by 
members of the G protein family. Dr. Sprang also 
maintains a long-term research program to study the 
allosteric mechanism of glycogen phosphorylase. 
High-resolution crystallography continues to pro- 
vide mechanistic insight into transcriptional regula- 
tion in the laboratory of Investigator Paul B. Sigler, 
M.D., Ph.D. (Yale University). Targeting of dimeric 
steroid/nuclear receptors to their DNA response ele- 
ments affirms the role of DNA in influencing discrim- 
inatory protein-protein interactions at the site of 
control. Studies of E2, the master transcription regu- 
lator of papillomavirus, reveal a heretofore unde- 
scribed structure — a dimeric /? barrel that serves 
as a scaffold for recognition helices and bends 
DNA. Crystallographic studies of the rhodopsin- 
transducin-cGMP phosphodiesterase (PD) -signal- 
ing system have progressed to 2 .0 A in the case of the 
activated G^^ • GTP complex. G„t • GTP has also been 
crystallized in a complex with its target, the 7 sub- 
unit of PD. 
The research of Investigator John W. Sedat, Ph.D. 
(University of California, San Francisco) and his col- 
leagues centers on the determination of eukaryotic 
chromosome structure using three-dimensional op- 
tical and electron microscopic approaches. This 
past year, development of multidimensional optical 
microscopy has made possible the analysis of the 
spatial and temporal dynamics of topoisomerase II 
and lamin nuclear proteins. The three-dimensional 
hybridization in situ of selected DNA probes in nu- 
clei within Drosophila embryos has been extended 
in order to investigate homologous chromosome 
pairing interactions. Work on the architecture and 
substructure determination of mitotic and meiotic 
chromosomes using combined optical and electron 
microscopic analysis is in progress. 
The laboratory of Associate Investigator David A. 
Agard, Ph.D. (University of California, San Fran- 
cisco) focuses on understanding the relationship be- 
tween structure and function at the cellular and mo- 
lecular levels. Recent work using IVEM tomography 
is providing new insights into higher order chromo- 
some structure. The group has also developed a 
novel theoretical approach that appears able to pre- 
dict accurately the functional consequences of a 
mutation. The unusual folding pathway of the pro- 
tein a-lytic protease has provided the laboratory 
with a unique opportunity to trap a stable folding 
intermediate under nondenaturing conditions and 
to study the foldase that converts it to the mature, 
active enzyme. In other studies the crystal structure 
of apolipoprotein E, an important protein in human 
cholesterol metabolism, along with several natu- 
rally occurring human mutations in this protein, 
have recently been solved by x-ray crystallography. 
STRUCTURAL BIOLOGY 459 
