of heparin. Efforts are also under way to prepare 
crystals of the extracellular domain of the fig gene 
product, which encodes the cellular receptor of 
FGF. FGF receptor, expressed in SF9 cells, is pro- 
vided by Dr. Phillip Barr (Chiron) . 
Crystallographic Analysis of GTP-binding 
Signal-Transduction Proteins 
Hormonal signals induced by growth factors such 
as those described above are, in many cases, cou- 
pled to intracellular transduction systems that in- 
volve members of the G protein family. A major in- 
terest of the Sprang laboratory has been to define the 
receptor, effector, and 187-binding domains of G 
protein a subunits and to understand the nature of 
the conformational changes induced by receptor- 
mediated GTP binding and subsequent GTP hydroly- 
sis. In collaboration with Dr. Alfred Gilman's labora- 
tory (University of Texas Southwestern Medical 
Center at Dallas), Dr. David Coleman has obtained 
crystals (space group P3i2j; a = 80. 1 A, i> = 106.3 
A) of the GTP-7S (a nonhydrolyzable analogue of 
GTP) complex of Gia that diffract beyond 2.4 A. Gi 
couples the activation of plasma membrane potas- 
sium channels to muscarinic receptors. 
Candidate heavy-atom derivatives have been pre- 
pared and data collected for solution of the struc- 
ture by heavy- atom techniques. The laboratory has 
also prepared crystals of two muteins of Gia. These 
muteins suffer from well-defined physicochemical 
lesions in GTP hydro lytic activity or activation. The 
structures of these molecules will illuminate the 
mechanisms of catalysis and signal transduction in 
this important class of proteins. 
Crystals have also been obtained of the a subunit 
of Gs, the heterotrimeric G protein that couples /3- 
adrenergic receptors to adenylyl cyclase. Intense 
efforts are under way, in collaboration with Dr. Gil- 
man's laboratory, to develop a productive expres- 
sion system for Gsa to generate sufficient quantities 
of Gsa for further cr}'stallographic studies. 
Mechanism of the Allosteric Transition 
in Glycogen Phosphorylase 
Last year the structure of the activated state of gly- 
cogen phosphorylase as induced by adenosine 
monophosphate was reported (with Drs. Elizabeth 
Goldsmith, Stephen Withers, and Robert Fletter- 
ick) . This and ongoing studies have yielded new in- 
formation about the nature of the allosteric transi- 
tion in this complex, cooperative enzyme. Previous 
descriptions of the phosphorylase active state have 
been extended by the demonstration of domain rear- 
rangements in the tertiary structure of the phos- 
phorylase subunits upon activation. The laboratory 
is now engaged in structural studies of the activated 
enzyme with bound substrates and transition-state 
analogues in order to elucidate the catalytic mecha- 
nism of this enzyme, which, despite 40 years of re- 
search by several dedicated laboratories throughout 
the world, remains poorly understood. 
Dr. Sprang is also Associate Professor of Bio- 
chemistry at the University of Texas Southwestern 
Medical Center at Dallas. 
Books and Chapters of Books 
Sprang, S.R., and Eck, M.J. 1992. The 3-D struc- 
ture ofTNF. In Tumor Necrosis Factors: The Mol- 
ecules and Their Emerging Role in Medicine 
(Beutler, B., Ed.). New York: Raven, pp 11-32. 
Articles 
Eck, M.J., Ultsch, M., Rinderknecht, E., de Vos, 
A.M., and Sprang, S.R. 1992. The structure of 
human lymphotoxin (tumor necrosis factor-/?) at 
1.9-A resolution./ 5/0/ Chem 267:2119-2122. 
Sprang, S.R. 1992. The latent tendencies of PAI-1. 
Trends Biochem Sci 17:49-50. 
Sprang, S.R., Withers, S.G., Goldsmith, E.J., Fletter- 
ick, R.J., and Madsen, N.B. 1991- Structural basis 
for the activation of glycogen phosphorylase b by 
adenosine monophosphate. Science 254:1367- 
1371. 
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