by phosphorylation, metabolites, and subunit 
cooperativity. More recently the laboratory has 
begun structural studies of G transduction proteins 
that couple the (3-adrenergic receptor to regulation 
of adenylate cyclase, thus initiating the cascade of 
phosphorylation events that results in the activa- 
tion of phosphorylase and many other enzymes. 
Structural studies have been initiated of cachectin, 
or tumor necrosis factor, which binds to a cellular 
receptor and initiates a series of complex metabolic 
changes characteristic of shock and inflammation. 
Studies of a new class of membrane-associated 
calcium-binding proteins that may play a signifi- 
cant role in membrane morphogenesis are also 
under way. 
The aim of the research of Investigator Paul B. 
Sigler, M.D., Ph.D. (Yale University) and his col- 
leagues is to understand cellular regulatory mecha- 
nisms in detailed chemical terms. Two processes re- 
ceive special attention: 1) transcription of the 
genetic message and 2) transduction of external sig- 
nals across the cell's membrane. Current research 
concerns the recognition by a regulator protein of 
genetic signals in the DNA, and the enzymatic 
mechanism of "second messenger" release. High- 
resolution x-ray crystallography is used to visualize, 
in detail, the molecular structures involved. From 
these structures, chemical mechanisms can be in- 
ferred and then checked, using biochemical and ge- 
netic methods. 
The general goal of the laboratory of Investigator 
Thomas A. Steitz, Ph.D. (Yale University) has been 
to understand the biological function of macromol- 
ecules in terms of their detailed molecular struc- 
ture. The work addresses the following questions 
about proteins that interact with nucleic acids: 
How do the sequence-specific DNA-binding pro- 
teins recognize the particular DNA sequence to 
which they bind? What are the common structural 
themes among proteins that interact with nucleic 
acids? How do the template-directed polymerases 
assure high fidelity in the copying of templates? The 
specific systems under study include the catabolite 
gene activator protein, the Klenow fragment of 
DNA polymerase I (in collaboration with Dr. Cath- 
erine Joyce), resolvase, recA, and tRNA*^'"-syn- 
thetase complex. To understand enzyme mecha- 
nisms. Dr. Steitz and his colleagues are using 
site-directed mutagenesis to determine the effect of 
specific mutations on the three-dimensional struc- 
ture of the protein and its complexes with sub- 
strates. 
563 
