Structural Studies of Regulatory Proteins 
tion or repair. Our work has lately focused on the 
interaction between bFGF and heparin, a com- 
plex, negatively charged sugar polymer that coats 
endothelial cells and is required to induce the 
mitogenic response that bFGF elicits. In a collabo- 
ration with Phillip Barr of Chiron, Inc., the labo- 
ratory is also attempting to determine the struc- 
ture of the receptor for bFGF. 
The signals generated by the engagement of ex- 
tracellular messenger molecules with their re- 
ceptors are, in many cases, transmitted across the 
plasma membrane to members of the G protein 
family. For example, when epinephrine binds to 
the /3-adrenergic receptor, an intracellular pro- 
tein called Gsa is induced to bind the nucleotide 
GTP and discard a pair of regulatory subunits. 
The GTP-bound Gsa is then an activator of a 
membrane-bound enzyme that catalyzes the syn- 
thesis of the intracellular messenger molecule 
cyclic AMP. In collaboration with Alfred Gilman 
(University of Texas Southwestern Medical 
Center at Dallas), we are undertaking crystallo- 
graphic studies of Gsa and the related protein 
Gia to learn how these proteins may interact with 
other components of the signal transduction sys- 
tem. Research Associate David Coleman has ob- 
tained small crystals of the complex between Gia 
and a nonhydrolyzable GTP analogue, and we 
hope soon to resolve the structure of this fascinat- 
ing molecule. 
Glycogen Phosphorylase 
A second focus of the laboratory has been to 
understand how a certain class of complex biolog- 
ical catalysts, called allosteric enzymes, regulate 
their own activity. An example of such an en- 
zyme, studied in our laboratory, is glycogen 
phosphorylase. This molecule catalyzes the 
breakdown of a storage carbohydrate called gly- 
cogen into sugar units that can be used directly by 
the body to fuel muscle contraction or to main- 
tain constant levels of glucose in the blood. The 
activity of this enzyme increases when it binds to 
"cellular messenger" molecules such as adeno- 
sine monophosphate, which signals an energy 
deficit in the cell, and decreases when it binds 
glucose, which signals an energy surplus. Glyco- 
gen phosphorylase can be chemically modified 
(phosphorylated) by other enzymes in response 
to hormonal signals (epinephrine), which also 
increases the catalytic activity of this enzyme. 
Our goal is to understand the molecular mechan- 
ics of the process by which catalytic machines 
such as phosphorylase can alter their activity in 
response to the cellular messengers. 
We have recently determined the three-dimen- 
sional structure of active glycogen phosphorylase 
with the activator AMP bound to a regulatory site 
in the molecule. In comparing this structure with 
the inactive conformation of the molecule deter- 
mined in Robert Fletterick's laboratory (Univer- 
sity of California, San Francisco) , we have learned 
how the three-dimensional structure of the mole- 
cule is altered in such a way as to increase the 
affinity of the enzyme for glycogen. 
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